Combination therapy for the treatment of diabetes

ABSTRACT

The present invention is directed to co-therapy and methods for the treatment and prevention of glucose-related disorders such as Type 2 diabetes mellitus and Syndrome X. The present invention is further directed to pharmaceutical compositions for the co-therapy and methods described herein.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application61/223,881, filed on Jul. 8, 2009, which is incorporated by referenceherein in its entirety.

FIELD OF THE INVENTION

The present invention is directed to co-therapy and methods for thetreatment and prevention of glucose-related disorders such as Type 2diabetes mellitus and Syndrome X. The present invention is furtherdirected to pharmaceutical compositions for the co-therapy and methodsdescribed herein.

BACKGROUND OF THE INVENTION

Diabetes mellitus is a medical term for the presence of elevated bloodglucose. People with diabetes either don't produce insulin, produce toolittle insulin or do not respond to insulin, resulting in the build upof glucose in the blood. The most common form of diabetes is Type 2diabetes, once referred to as adult onset diabetes or non-insulindependent diabetes (NIDDM), which may account for >90% of diabetes inadults. However, as the younger population becomes increasinglyoverweight or obese, Type 2 diabetes is becoming more prevalent in teensand children. Diabetes may also refer to gestational diabetes, Type 1diabetes or autoimmune diabetes, once referred to as juvenile onsetdiabetes and type 1½ diabetes, also referred to as latent-autoimmunediabetes in adults or LADA. Diabetes may occur because of poor dietaryhabits or lack of physical activity (e.g., sedentary lifestyle), geneticmutations, injury to the pancreas, drug (e.g., AIDS therapies) orchemical (e.g., steroid) exposure or disease (e.g., cystic fibrosis,Down syndrome, Cushing's syndrome). Two rare types of genetic defectsleading to diabetes are termed maturity-onset diabetes of the young(MODY) and atypical diabetes mellitus (ADM).

Type 2 diabetes mellitus (non-insulin-dependent diabetes mellitus orNIDDM) is a metabolic disorder involving disregulation of glucosemetabolism and insulin resistance, and long-term complications involvingthe eyes, kidneys, nerves, and blood vessels. Type 2 diabetes mellitususually develops in adulthood (middle life or later) and is described asthe body's inability to make either sufficient insulin (abnormal insulinsecretion) or its inability to effectively use insulin (resistance toinsulin action in target organs and tissues). More particularly,patients suffering from Type 2 diabetes mellitus have a relative insulindeficiency. That is, in these patients, plasma insulin levels are normalto high in absolute terms, although they are lower than predicted forthe level of plasma glucose that is present.

Type 2 diabetes mellitus is characterized by the following clinicalsigns or symptoms: persistently elevated plasma glucose concentration orhyperglycemia; polyuria; polydipsia and/or polyphagia; chronicmicrovascular complications such as retinopathy, nephropathy andneuropathy; and macrovascular complications such as hyperlipidemia andhypertension which can lead to blindness, end-stage renal disease, limbamputation and myocardial infarction.

Syndrome X, also termed Insulin Resistance Syndrome (IRS), MetabolicSyndrome, or Metabolic Syndrome X, is a disorder that presents riskfactors for the development of Type 2 diabetes mellitus andcardiovascular disease including glucose intolerance, hyperinsulinemiaand insulin resistance, hypertriglyceridemia, hypertension and obesity.

The diagnosis of Type 2 diabetes mellitus includes assessment ofsymptoms and measurement of glucose in the urine and blood. Bloodglucose level determination is necessary for an accurate diagnosis. Morespecifically, fasting blood glucose level determination is a standardapproach used. However, the oral glucose tolerance test (OGTT) isconsidered to be more sensitive than fasted blood glucose level. Type 2diabetes mellitus is associated with impaired oral glucose tolerance(OGT). The OGTT thus can aid in the diagnosis of Type 2 diabetesmellitus, although generally not necessary for the diagnosis of diabetes(Emancipator K, Am J Clin Pathol 1999 November; 112(5):665-74; Type 2Diabetes Mellitus, Decision Resources Inc., March 2000). The OGTT allowsfor an estimation of pancreatic beta-cell secretory function and insulinsensitivity, which helps in the diagnosis of Type 2 diabetes mellitusand evaluation of the severity or progression of the disease (e.g.,Caumo A, Bergman R N, Cobelli C, J Clin Endocrinol Metab 2000, 85(11):4396-402). More particularly, the OGTT is extremely helpful inestablishing the degree of hyperglycemia in patients with multipleborderline fasting blood glucose levels that have not been diagnosed asdiabetics. In addition, the OGTT is useful in testing patients withsymptoms of Type 2 diabetes mellitus where the possible diagnosis ofabnormal carbohydrate metabolism has to be clearly established orrefuted.

Thus, impaired glucose tolerance is diagnosed in individuals that havefasting blood glucose levels less than those required for a diagnosis ofType 2 diabetes mellitus, but have a plasma glucose response during theOGTT between normal and diabetics. Impaired glucose tolerance isconsidered a pre-diabetic condition, and impaired glucose tolerance (asdefined by the OGTT) is a strong predictor for the development of Type 2diabetes mellitus (Haffner S M, Diabet Med 1997 August; 14 Suppl3:S12-8).

Type 2 diabetes mellitus is a progressive disease associated with thereduction of pancreatic function and/or other insulin-related processes,aggravated by increased plasma glucose levels. Thus, Type 2 diabetesmellitus usually has a prolonged pre-diabetic phase and variouspathophysiological mechanisms can lead to pathological hyperglycemia andimpaired glucose tolerance, for instance, abnormalities in glucoseutilization and effectiveness, insulin action and/or insulin productionin the prediabetic state (Goldberg R B, Med Clin North Am 1998 July;82(4):805-21).

The pre-diabetic state associated with glucose intolerance can also beassociated with a predisposition to abdominal obesity, insulinresistance, hyperlipidemia, and high blood pressure, that is, Syndrome X(Groop L, Forsblom C, Lehtovirta M, Am J Hypertens 1997 September; 10(9Pt 2):1725-1805; Haffner S M, J Diabetes Complications 1997 March-April;11(2):69-76; Beck-Nielsen H, Henriksen J E, Alford F, Hother-Nielson O,Diabet Med 1996 September; 13(9 Suppl 6):578-84).

Thus, defective carbohydrate metabolism is pivotal to the pathogenesisof Type 2 diabetes mellitus and impaired glucose tolerance (Dinneen S F,Diabet Med 1997 August; 14 Suppl 3:S19-24). In fact, a continuum fromimpaired glucose tolerance and impaired fasting glucose to definitiveType 2 diabetes mellitus exists (Ramlo-Halsted B A, Edelman S V, PrimCare 1999 December; 26(4):771-89).

Early intervention in individuals at risk to develop Type 2 diabetesmellitus, focusing on reducing the pathological hyperglycemia orimpaired glucose tolerance may prevent or delay the progression towardsType 2 diabetes mellitus and associated complications and/or Syndrome X.Therefore, by effectively treating impaired oral glucose toleranceand/or elevated blood glucose levels, one can prevent or inhibit theprogression of the disorder to Type 2 diabetes mellitus or Syndrome X.

Typical treatment of glucose disorders including Type 2 diabetesmellitus and Syndrome X focuses on maintaining the blood glucose levelas near to normal as possible and includes diet and exercise, and whennecessary, treatment with anti-diabetic agents, insulin or a combinationthereof. Type 2 diabetes mellitus that cannot be controlled by dietarymanagement is treated with oral antidiabetic agents including, but notlimited to, sulfonylureas (e.g., not limited to first generation:chlorpropamide, tolazamide, tolbutamide; second generation: glyburide,glipizide; and third generation: glimepiride), biguanides (e.g.,metformin), thiazolidinediones (e.g., rosiglitazone, pioglitazone,troglitazone), alpha-glucosidase inhibitors (e.g., acarbose, miglitol),meglitinides (e.g., repaglinide), other insulin-sensitizing compounds,and/or other anti-obesity agents (e.g., orlistat or sibutramine). ForSyndrome X, the anti-diabetic agents are additionally combined withpharmacological agents for the treatment of the concomitantco-morbidities (e.g., antihypertensives for hypertension, hypolipidemicagents for hyperlipidemia).

First-line therapies typically include metformin and sulfonylureas aswell as thiazolidinediones. Metformin monotherapy is a first linechoice, particularly for treating Type 2 diabetic patients who are alsoobese and/or dyslipidemic. Lack of an appropriate response to metforminis often followed by treatment with metformin in combination withsulfonylureas, thiazolidinediones, or insulin. Sulfonylurea monotherapy(including all generations of drugs) is also a common first line option.Another first line therapy choice may be thiazolidinediones. Patientswho do not respond appropriately to oral anti-diabetic monotherapy, aregiven combinations of these agents. When glycemic control cannot bemaintained with oral antidiabetics alone, insulin therapy is used eitheras a monotherapy, or in combination with oral antidiabetic agents. Thesesame strategies, optionally in combination with additional strategies(e.g., anti-hypertensive) can be used for the treatment of Syndrome X.

Anti-diabetic agents include, but are not limited to:

(a) Sulfonylureas, which increase insulin production by stimulatingpancreatic beta cells, and therefore act as insulin secretagogues. Theprimary mechanism of action of sulfonylureas is to close ATP-sensitivepotassium channels in the beta-cell plasma membrane, initiating a chainof events that result in insulin release. Suitable examples ofsulfonylureas include, but are not limited to chlorpropamide,tolazamide, tolbutamide, glyburide, glipizide, glimepiride, and like.

(b) Meglitinides, another class of insulin secretagogues, that have amechanism of action distinct from that of the sulfonylureas. Suitableexamples of meglitinides include, but are not limited to repaglinide.

(c) Agents which modify insulin secretion such as Glucagon-likePeptide-1 (GLP-1) and it's mimetics, Glucose-insulinotropic peptide(GIP) and it's mimetics, Exendin and it's mimetics, and DipeptylProtease Inhibitors (DPPIV).

(d) Biguanides which decrease liver glucose production and increase theuptake of glucose. Suitable examples include, but are not limited tometformin.

(e) Thiazolidinediones, insulin sensitizing drugs which decreaseperipheral insulin resistance by enhancing the effects of insulin attarget organs and tissues. These drugs bind and activate the nuclearreceptor, peroxisome proliferator-activated receptor-gamma (PPAR-gamma)which increases transcription of specific insulin-responsive genes.Suitable examples of PPAR-gamma agonists are the thiazolidinedioneswhich include, but are not limited to rosiglitazone, pioglitazone,troglitazone, isaglitazone (known as MCC-555),2-[2-[(2R)-4-hexyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazin-2-yl]ethoxy]-benzeneacetic acid, and the like. Additionally, the non-thiazolidinediones alsoact as insulin sensitizing drugs, and include, but are not limited toGW2570, and the like.

(f) Retinoid-X receptor (RXR) modulators, also insulin sensitizingdrugs, which include, but are not limited to targretin, 9-cis-retinoicacid, and the like.

(g) Other insulin sensitizing agents include, but are not limited toINS-1, PTP-1B inhibitors, GSK3 inhibitors, glycogen phosphorylase ainhibitors, fructose-1,6-bisphosphatase inhibitors, and the like.

(h) Alpha-glucosidase inhibitors which act to inhibit alpha-glucosidase.Alpha-glucosidase converts fructose to glucose, thus these inhibitorsdelay the digestion of carbohydrates. The undigested carbohydrates aresubsequently broken down in the gut, thereby reducing the post-prandialglucose peak. Suitable examples include, but are not limited to,acarbose and miglitol.

(i) Insulins, including regular or short-acting, intermediate-acting,and long-acting insulins, inhaled insulin and insulin analogues such asinsulin molecules with minor differences in the natural amino acidsequence. These modified insulins may have faster onset of action and/orshorter duration of action.

(j) Small molecule mimics of insulin, including, but not limited toL-783281, TE-17411, and the like.

(k) Na-glucose co-transporter inhibitors which inhibit the renalreabsorption of glucose such as T-1095, T-1095A, phlorizin, and thelike.

(l) Amylin agonists which include, but are not limited to pramlintide,and the like.

(k) Glucagon antagonists such as AY-279955, and the like.

In addition to antidiabetic agents, therapies may include add-ontreatment with anti-obesity agents such as orlistat, a pancreatic lipaseinhibitor, which prevents the breakdown and absorption of fat; orsibutramine, an appetite suppressant and inhibitor of the reuptake ofserotonin, norepinephrine and dopamine in the brain. Other potentialadd-on anti-obesity agents include, but are not limited to,appetite-suppressants acting through adrenergic mechanisms such asbenzphetamine, phenmetrazine, phentermine, diethylpropion, mazindol,sibutramine, phenylpropanolamine or, ephedrine; appetite-suppressantagents acting through serotonergic mechanisms such as quipazine,fluoxetine, sertraline, fenfluramine, or dexfenfluramine;appetite-suppressant agents acting through dopamine mechanisms, eg,apomorphine; appetite-suppressant agents acting through histaminergicmechanisms (eg, histamine mimetics, H3 receptor modulators); enhancersof energy expenditure such as beta-3 adrenergic agonists and stimulatorsof uncoupling protein function; leptin and leptin mimetics; neuropeptideY antagonists; melanocortin-1, 3 and 4 receptor modulators;cholecystokinin agonists; glucagon-like peptide-1 (GLP-1) mimetics andanalogues (eg, Exendin); androgens (eg, dehydroepiandrosterone andderivatives such as etiocholandione), testosterone, anabolic steroids(eg, oxandrolone), and steroidal hormones; galanin receptor antagonists;cytokine agents such as ciliary neurotrophic factor; amylase inhibitors;enterostatin agonists/mimetics; orexin/hypocretin antagonists; urocortinantagonists; bombesin agonists; modulators of protein kinase A;corticotropin-releasing factor mimetics; cocaine- andamphetamine-regulated transcript mimetics; calcitonin-gene relatedpeptide mimetics; and fatty acid synthase inhibitors.

There remains a need to provide an effective treatment for glucoserelated disorders such as elevated glucose levels, Type 2 diabetesmellitus, Syndrome X, and the like. There also remains a need to providean effective treatment for glucose related disorders which also slows orprevents the progression and/or development of Type 2 diabetes mellitus.

SUMMARY OF THE INVENTION

The present invention is directed to methods of co-therapy for thetreatment and prevention of glucose-related disorders, said methodscomprising administering to a subject in need thereof a therapeuticallyeffective amount of co-therapy comprising (a) metformin or apharmaceutically acceptable salt thereof and (b) a compound of formula(I)

wherein Ring A and Ring B are one of the followings:

(1) Ring A is an optionally substituted unsaturated monocyclicheterocyclic ring, and Ring B is an optionally substituted unsaturatedmonocyclic heterocyclic ring, an optionally substituted unsaturatedfused heterobicyclic ring, or an optionally substituted benzene ring; or

(2) Ring A is an optionally substituted benzene ring, and Ring B is anoptionally substituted unsaturated monocyclic heterocyclic ring, or anoptionally substituted unsaturated fused heterobicyclic ring wherein Yis linked to the heterocyclic ring of the fused heterobicyclic ring; or

(3) Ring A is an optionally substituted unsaturated fused heterobicyclicring, wherein the sugar moiety X-(sugar) and the moiety —Y-(Ring B) areboth on the same heterocyclic ring of the fused heterobicyclic ring, andRing B is an optionally substituted unsaturated monocyclic heterocyclicring, an optionally substituted unsaturated fused heterobicyclic ring,or an optionally substituted benzene ring;

X is a carbon atom or a nitrogen atom; and

Y is —(CH₂)_(n)— (wherein n is 1 or 2);

or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

The present invention is further directed to methods of co-therapy forthe treatment and prevention of glucose-related disorders, said methodscomprising administering to a subject in need thereof a therapeuticallyeffective amount of co-therapy comprising (a) glyburide and (b) acompound of formula (I) or pharmaceutically acceptable salt thereof.

The present invention is further directed to (a) a compound of formula(I) or pharmaceutically acceptable salt thereof in combination with (b)metformin or a pharmaceutically acceptable salt thereof for use in thetreatment and prevention of glucose-related disorders

The present invention is further directed to (a) a compound of formula(I) or pharmaceutically acceptable salt thereof in combination with (b)metformin or a pharmaceutically acceptable salt thereof and (c) asulfonylurea (preferably glyburide) or pharmaceutically acceptable saltthereof for use in the treatment and prevention of glucose-relateddisorders.

The present invention is further directed to methods of co-therapy forthe treatment and prevention of glucose-related disorders, said methodscomprising administering to a subject in need thereof a therapeuticallyeffective amount of co-therapy comprising (a) metformin or apharmaceutically acceptable salt thereof and (b) a compound of formula(I) or pharmaceutically acceptable salt thereof and (c) a sulfonylurea(preferably glyburide) or pharmaceutically acceptable salt thereof.

The present invention is further directed to a pharmaceuticalcomposition comprising (a) metformin or a pharmaceutically acceptablesalt thereof, (b) a compound of formula (I) or pharmaceuticallyacceptable salt thereof and (c) a pharmaceutically acceptable excipient.An illustration of the invention is a pharmaceutical composition made bymixing comprising (a) metformin or a pharmaceutically acceptable saltthereof, (b) a compound of formula (I) or pharmaceutically acceptablesalt thereof and (c) a pharmaceutically acceptable excipient.Illustrating the invention is a process for making a pharmaceuticalcomposition comprising mixing comprising (a) metformin or apharmaceutically acceptable salt thereof, (b) a compound of formula (I)or pharmaceutically acceptable salt thereof and (c) a pharmaceuticallyacceptable excipient.

The present invention is further directed to a pharmaceuticalcomposition comprising (a) a sulfonylurea (preferably glyburide) or apharmaceutically acceptable salt thereof, (b) a compound of formula (I)or pharmaceutically acceptable salt thereof and (c) a pharmaceuticallyacceptable excipient. An illustration of the invention is apharmaceutical composition made by mixing comprising (a) a sulfonylurea(preferably glyburide) or a pharmaceutically acceptable salt thereof,(b) a compound of formula (I) or pharmaceutically acceptable saltthereof and (c) a pharmaceutically acceptable excipient. Illustratingthe invention is a process for making a pharmaceutical compositioncomprising mixing comprising (a) a sulfonylurea (preferably glyburide)or a pharmaceutically acceptable salt thereof, (b) a compound of formula(I) or pharmaceutically acceptable salt thereof and (c) apharmaceutically acceptable excipient.

The present invention is further directed to a pharmaceuticalcomposition comprising (a) metformin or a pharmaceutically acceptablesalt thereof, (b) a compound of formula (I) or pharmaceuticallyacceptable salt thereof, (c) a sulfonylurea or pharmaceuticallyacceptable salt thereof, and (d) a pharmaceutically acceptableexcipient. An illustration of the invention is a pharmaceuticalcomposition made by mixing comprising (a) metformin or apharmaceutically acceptable salt thereof, (b) a compound of formula (I)or pharmaceutically acceptable salt thereof, (c) a sulfonylurea orpharmaceutically acceptable salt thereof, and (d) a pharmaceuticallyacceptable excipient. Illustrating the invention is a process for makinga pharmaceutical composition comprising mixing comprising (a) metforminor a pharmaceutically acceptable salt thereof, (b) a compound of formula(I) or pharmaceutically acceptable salt thereof, (c) a sulfonylurea orpharmaceutically acceptable salt thereof, and (d) a pharmaceuticallyacceptable excipient.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to methods for the treatment andprevention of glucose related disorders comprising administering to asubject in need thereof a therapeutically effective amount of co-therapycomprising (a) metformin or a pharmaceutically acceptable salt thereofand (b) a compound of formula (I)

wherein Ring A, Ring B, X and Y are as herein defined; orpharmaceutically acceptable salt thereof.

The compounds of the formula (I) exhibit an inhibitory activity againstsodium-dependent glucose transporter, such as for example SGLT2. Thecompounds of formula (I) exhibit an inhibitory activity againstsodium-dependent glucose transporter, present in the intestine and thekidney of mammalian species, and further exhibit a blood glucoselowering effect. The compounds of formula (I) may be prepared accordingto the process as disclosed in Nomura, S. et al., US Patent Publication,US 2005/0233988 A1, published Oct. 20, 2005, which is incorporated byreference herein.

In an embodiment, the present invention is directed to methods for thetreatment and prevention of glucose related disorders comprisingadministering to a subject in need thereof a therapeutically effectiveamount of co-therapy comprising (a) metformin or a pharmaceuticallyacceptable salt thereof and (b) a compound of formula (I-X)

or pharmaceutically acceptable salt thereof. In certain preferredembodiments, the compound of formula (I-X) is the crystalline form ofthe hemihydrate of the compound of Formula (I-X), as described in WO2008/069327, the disclosure of which is hereby incorporated by referencein its entirety.

In another embodiment, the present invention is directed to methods forthe treatment and prevention of glucose related disorders comprisingadministering to a subject in need thereof a therapeutically effectiveamount of co-therapy comprising (a) metformin or a pharmaceuticallyacceptable salt thereof and (b) a compound of formula (I-Y)

or pharmaceutically acceptable salt thereof.

The present invention is further directed to methods for the treatmentand prevention of glucose related disorders comprising administering toa subject in need thereof a therapeutically effective amount ofco-therapy comprising (a) a sulfonylurea (preferably glyburide) or apharmaceutically acceptable salt thereof, and (b) a compound of formula(I)

wherein Ring A, Ring B, X and Y are as herein defined; orpharmaceutically acceptable salt thereof. In another embodiment, thepresent invention is directed to methods for the treatment andprevention of glucose related disorders comprising administering to asubject in need thereof a therapeutically effective amount of co-therapycomprising (a) a sulfonylurea (preferably glyburide) or apharmaceutically acceptable salt thereof, and (b) a compound of formula(I-X) or pharmaceutically acceptable salt thereof. In anotherembodiment, the present invention is directed to methods for thetreatment and prevention of glucose related disorders comprisingadministering to a subject in need thereof a therapeutically effectiveamount of co-therapy comprising (a) a sulfonylurea (preferablyglyburide) or a pharmaceutically acceptable salt thereof, and (b) acompound of formula (I-Y) or pharmaceutically acceptable salt thereof.

Metformin and more particularly metformin hydrochloride, (also known bythe trade names GLUCOPHAGE, RIOMET, FORTAMET, GLUMETZA, OBIMET, DIANBEN,DIABEX, DIAFORMIN, and others) is an oral anti-diabetic drug of thebiguanide class. Metformin is a first-line therapy for Type 2 diabetesmellitis, particularly in overweight and obese people. The usualstarting dose of metformin (for example, as metformin hydrochloridetablets) in the United States and certain other countries is 500 mgtwice a day or 850 mg once a day, given with meals. The daily dosage maybe increases in increments of 500 mg weekly or 850 mg every 2 weeks, upto a total of 2000 mg per day, given in divided doses. Patients can alsobe titrated from 500 mg twice a day to 850 mg twice a day after 2 weeks.For those patients requiring additional glycemic control, metformin maybe given to a maximum daily dose of 2550 mg per day. Doses above 2000 mgmay be better tolerated given three times a day with meals. Preferably,the metformin or pharmaceutically acceptable salt thereof is metforminhydrochloride.

Glyburide (also known as glibenclamide, and further known by the tradenames DIABETA, GLYNASE PRESTAB, MICRONASE and others) is an oralanti-diabetic of the sulfonylurea class. Glyburide is used for thetreatment of Type II diabetes mellitus and works by inhibitingATP-sensitive potassium channels in pancreatic beta cells. Thisinhibition causes cell membrane depolarization, which causesvoltage-dependent calcium channels to open, which in turn causes anincrease in intracellular calcium in the beta cell, which stimulatesinsulin release. The starting dosage for glyburide is typically 2.5 mgto 5 mg (1.5 gm to 3 mg, if administered as micronized glyburide) takendaily with meals. As needed, glyburide dosages may be graduallyincreased (in steps of 2.5 mg or less per week) up to 20 mg daily (or upto 12 mg daily if administered as micronized glyburide). Glyburide mayalso be administered in combination with metformin, and is available asin combination with metformin under the trade names GLUCOVANCE andGLIBOMET.

The present invention is further directed to methods for the treatmentand prevention of glucose related disorders comprising administering toa subject in need thereof a therapeutically effective amount ofco-therapy comprising (a) metformin or a pharmaceutically acceptablesalt thereof and (b) a compound of formula (I) or pharmaceuticallyacceptable salt thereof, and (c) a sulfonylurea or pharmaceuticallyacceptable salt thereof.

In an embodiment, the present invention is directed to methods for thetreatment and prevention of glucose related disorders comprisingadministering to a subject in need thereof a therapeutically effectiveamount of co-therapy comprising (a) metformin or a pharmaceuticallyacceptable salt thereof and (b) a compound of formula (I-X) orpharmaceutically acceptable salt thereof, and (c) a sulfonylurea orpharmaceutically acceptable salt thereof.

In another embodiment, the present invention is directed to methods forthe treatment and prevention of glucose related disorders comprisingadministering to a subject in need thereof a therapeutically effectiveamount of co-therapy comprising (a) metformin or a pharmaceuticallyacceptable salt thereof and (b) a compound of formula (I-Y) orpharmaceutically acceptable salt thereof, and (c) a sulfonylurea orpharmaceutically acceptable salt thereof.

The present invention is further directed to methods for the treatmentand prevention of glucose related disorders comprising administering toa subject in need thereof a therapeutically effective amount ofco-therapy comprising (a) metformin or a pharmaceutically acceptablesalt thereof and (b) a compound of formula (I) or pharmaceuticallyacceptable salt thereof, and (c) glyburide.

In another embodiment, the present invention is directed to methods forthe treatment and prevention of glucose related disorders comprisingadministering to a subject in need thereof a therapeutically effectiveamount of co-therapy comprising (a) metformin or a pharmaceuticallyacceptable salt thereof and (b) a compound of formula (I-X) orpharmaceutically acceptable salt thereof, and (c) glyburide.

In another embodiment, the present invention is directed to methods forthe treatment and prevention of glucose related disorders comprisingadministering to a subject in need thereof a therapeutically effectiveamount of co-therapy comprising (a) metformin or a pharmaceuticallyacceptable salt thereof and (b) a compound of formula (I-Y) orpharmaceutically acceptable salt thereof, and (c) glyburide.

Sulfonylureas are a class of pharmaceutical compounds which increaseinsulin production by stimulating pancreatic beta cells, and thereforeact as insulin secretagogues. The primary mechanism of action ofsulfonylureas is to close ATP-sensitive potassium channels in thebeta-cell plasma membrane, initiating a chain of events that result ininsulin release. Suitable examples of sulfonylureas include, but are notlimited to chlorpropamide, tolazamide, tolbutamide, glyburide,glipizide, glimepiride, and like. One skilled in the art can readilydetermine dosages and regimens for the administration of sulfonylureas,for example by consulting the PDR (Physician's Desk Reference) and/orthe FDA required drug literature included with the pharmaceutical agent.For example, a representative dosage for chlorpropamide (DIABINESE®) is100-250 mg QD; for tolazamide (TOLINASE®) is 250 mg QD or BID; fortolbutamide (ORINASE®) is 1000 mg BID or TID; for glimepiride (AMARYL®)is 2 mg QD; for glipizide (GLUCOTROL®) is 5-10 mg QD or BID; and forglyburide (DIABETA®, MICRONASE®) is 2.5-5 mg QD or BID.

In an embodiment of the present invention, the sulfonylurea is selectedfrom the group consisting of chlorpropamide, tolazamide and tolbutamide;wherein the sulfonylurea is present in (administered in) an amount inthe range of from about 100 mg to about 3000 mg, or any amount or rangetherein, preferably in an amount in the range of from about 100 mg toabout 1000 mg, or any amount or range therein. In another embodiment ofthe present invention, the sulfonylurea is selected from the groupconsisting of glyburide, glipizide and glimepiride; and is present in anamount in the range of from about 0.1 mg to about 50 mg, or any amountor range therein, preferably in an amount in the range of from about 1.0mg to about 50 mg, more preferably in an amount in the range of fromabout 2.0 mg to about 25 mg, or any amount or range therein.

In another embodiment of the present invention, the sulfonylurea isglyburide; wherein the glyburide is present in (administered in) anamount in the range of from about 1.0 mg to about 20 mg daily, or anyamount or range therein; preferably in an amount in the range of fromabout 2.5 mg to about 20 mg, daily, or any amount or range therein, morepreferably in an amount in the range of from about 2.5 mg to about 10 mgdaily, or any amount or range therein, more preferably in an amount inthe range of from about 2.5 mg to about 5 mg daily, or any amount orrange therein.

The present invention is further directed to a pharmaceuticalcomposition comprising a therapeutically effective amount of co-therapycomprising (a) metformin or a pharmaceutically acceptable salt thereof;and (b) a compound of formula (I) or pharmaceutically acceptable saltthereof. The present invention is further directed to a pharmaceuticalcomposition comprising a therapeutically effective amount of co-therapycomprising (a) glyburide; and (b) a compound of formula (I) orpharmaceutically acceptable salt thereof.

The present invention is further directed to a pharmaceuticalcomposition comprising a therapeutically effective amount of co-therapycomprising (a) metformin or a pharmaceutically acceptable salt thereof;(b) a compound of formula (I) or pharmaceutically acceptable saltthereof, and (c) a sulfonylurea or pharmaceutically acceptable saltthereof.

In an embodiment, the present invention is directed to a pharmaceuticalcomposition comprising (a) metformin or a pharmaceutically acceptablesalt thereof and (b) a compound of formula (I-X) or pharmaceuticallyacceptable salt thereof. In another embodiment, the present invention isdirected to a pharmaceutical composition comprising (a) metformin or apharmaceutically acceptable salt thereof and (b) a compound of formula(I-Y) or pharmaceutically acceptable salt thereof. In another embodimentof the present invention, the pharmaceutical composition is an immediaterelease dosage form. In another embodiment of the present invention, thepharmaceutical composition is an extended release dosage form, whereinthe dosage form releases the one or more of the active ingredients overa period of time in the range of from about 8 to about 24 hours, or anyamount or range therein.

In an embodiment, the present invention is directed to a pharmaceuticalcomposition comprising (a) glyburide and (b) a compound of formula (I-X)or pharmaceutically acceptable salt thereof. In another embodiment, thepresent invention is directed to a pharmaceutical composition comprising(a) glyburide and (b) a compound of formula (I-Y) or pharmaceuticallyacceptable salt thereof. In another embodiment of the present invention,said pharmaceutical composition is an immediate release dosage form. Inanother embodiment of the present invention, the pharmaceuticalcomposition is an extended release dosage form, wherein the dosage formreleases the one or more of the active ingredients over a period of timein the range of from about 8 to about 24 hours, or any amount or rangetherein.

In an embodiment, the present invention is directed to a pharmaceuticalcomposition comprising (a) metformin or a pharmaceutically acceptablesalt thereof, (b) a compound of formula (I-X) or pharmaceuticallyacceptable salt thereof, and (c) a sulfonylurea or pharmaceuticallyacceptable salt thereof. In another embodiment, the present invention isdirected to a pharmaceutical composition comprising (a) metformin or apharmaceutically acceptable salt thereof, (b) a compound of formula(I-Y) or pharmaceutically acceptable salt thereof, and (c) asulfonylurea or pharmaceutically acceptable salt thereof. In anotherembodiment of the present invention, the pharmaceutical composition isan immediate release dosage form. In another embodiment of the presentinvention, the pharmaceutical composition is an extended release dosageform, wherein the dosage form releases one or more of the activeingredients over a period of time in the range of from about 8 to about24 hours, or any amount or range therein, preferably over a time in therange of from about 8 hours to about 12 hours, or any amount or rangetherein.

In an embodiment, the present invention is directed to a pharmaceuticalcomposition wherein the metformin or pharmaceutically acceptable saltthereof is metformin hydrochloride. In another embodiment, the presentinvention is directed to a pharmaceutical composition wherein themetformin hydrochloride is present at a dosage amount in the range offrom about 100 mg to about 2000 mg, preferably from about 250 mg toabout 2000 mg, preferably from about 250 mg to about 1000 mg, or anyamount or range therein. In another embodiment, the present invention isdirected to a pharmaceutical composition wherein the metforminhydrochloride is present at a dosage amount selected from the groupconsisting of 250 mg, 500 mg, 750 mg, 850 mg, 1000 mg, 1700 mg and 2000mg.

In an embodiment, the present invention is directed to a pharmaceuticalcomposition wherein the glyburide is present at a dosage amount in therange of from about 1.0 mg to about 20.0 mg, preferably from about 2.5mg to about 20.0 mg, more preferably from about 2.5 mg to about 10.0 mg,or any amount or range therein. In another embodiment, the presentinvention is directed to a pharmaceutical composition wherein theglyburide is present at a dosage amount selected from the groupconsisting of 1.0, 1.5, 2.5, 5.0, 7.5, 10, 12.5, 15 and 20 mg.

In an embodiment, the present invention is directed to a pharmaceuticalcomposition wherein the compound of formula (I) or pharmaceuticallyacceptable salt thereof is selected from the group consisting of acompound of formula (I-X) or pharmaceutically acceptable salt thereof;and a compound of formula (I-Y) or pharmaceutically acceptable saltthereof. In another embodiment, the present invention is directed to apharmaceutical composition wherein the compound of formula (I) orpharmaceutically acceptable salt thereof is the compound of formula(I-X) or pharmaceutically acceptable salt thereof.

In another embodiment, the present invention is directed to apharmaceutical composition wherein the compound of formula (I-X) orpharmaceutically acceptable salt thereof is present at a dosage amountin the range of from about 1 mg to about 500 mg, preferably from about 1mg to about 300 mg, preferably from about 25 mg to about 300 mg, or anyamount or range therein. In another embodiment, the present invention isdirected to a pharmaceutical composition wherein the compound of formula(I-X) or pharmaceutically acceptable salt thereof is present at a dosageamount in the range of from about 25 mg to about 300 mg, preferablyselected from the group consisting of 50 mg, 100 mg, 150 mg, 200 mg and300 mg.

In another embodiment, the present invention is directed to apharmaceutical composition wherein the compound of formula (I-Y) orpharmaceutically acceptable salt thereof is present at a dosage amountin the range of from 1 mg to about 500 mg, preferably from about 1 mg toabout 100 mg, or from about 1 mg to about 50 mg, or any amount or rangetherein. In another embodiment, the present invention is directed to apharmaceutical composition wherein the compound of formula (I-Y) orpharmaceutically acceptable salt thereof is present at a dosage amountselected from the group consisting of 1 mg, 5 mg, 10 mg, 25 mg, 50 mgand 100 mg.

In yet another embodiment, the present invention is directed to apharmaceutical composition comprising:

(a) metformin or a pharmaceutically acceptable salt thereof;

(b) a compound of formula (I) or pharmaceutically acceptable saltthereof selected from the group consisting of a compound of formula(I-X) or pharmaceutically acceptable salt thereof; and a compound offormula (I-Y) or pharmaceutically acceptable salt thereof;

wherein the metformin or pharmaceutically acceptable salt thereof ispresent in an amount in the range of from about 100 mg to about 2000 mg,preferably from about 500 mg to about 1000 mg, or any amount or rangetherein; and

wherein the compound of formula (I) or pharmaceutically acceptable saltthereof is present in an amount in the range of from about 1 mg to about1000 mg, or any amount or range therein (preferably in an amount in therange of from about 1 mg to about 500 mg, or any amount or rangetherein, more preferably in an amount in the range of from about 10 mgto about 300 mg, or any amount or range therein).

In yet another embodiment, the present invention is directed to apharmaceutical composition comprising:

(a) glyburide; wherein the glyburide is present in an amount in therange of from about 1.0 mg to about 20 mg, preferably from about 2.5 mgto about 20 mg, or any amount or range therein; and

(b) a compound of formula (I) or pharmaceutically acceptable saltthereof (wherein the compound of formula (I) or pharmaceuticallyacceptable salt thereof is preferably selected from the group consistingof a compound of formula (I-X) or pharmaceutically acceptable saltthereof; and a compound of formula (I-Y) or pharmaceutically acceptablesalt thereof); wherein the compound of formula (I) or pharmaceuticallyacceptable salt thereof is present in an amount in the range of fromabout 1 mg to about 1000 mg, or any amount or range therein (preferablyin an amount in the range of from about 1 mg to about 500 mg, or anyamount or range therein, more preferably in an amount in the range offrom about 10 mg to about 300 mg, or any amount or range therein).

In an embodiment of the present invention, the compound of formula (I)is a compound of formula (I-X) and is present in the pharmaceuticalcomposition in an amount in the range of from about 1 mg to about 1000mg, or any amount or range therein, preferably in an amount in the rangeof from about 50 mg to about 300 mg, or any amount or range therein. Inanother embodiment of the present invention, the compound of formula (I)is a compound of formula (I-Y) and is present in the pharmaceuticalcomposition in an amount in the range of from about 1 mg to about 1000mg, or any amount or range therein, preferably in an amount in the rangeof from about 1 mg to about 100 mg, or any amount or range therein, morepreferably in an amount in the range of from about 10 mg to about 50 mg,or any range thereof.

In yet another embodiment, the present invention is directed to apharmaceutical composition comprising:

(a) metformin or a pharmaceutically acceptable salt thereof; wherein themetformin or pharmaceutically acceptable salt thereof is present in anamount in the range of from about 100 mg to about 2000 mg, preferablyfrom about 500 mg or about 1000 mg, or any amount or range therein;

(b) a compound of formula (I) or pharmaceutically acceptable saltthereof (wherein the compound of formula (I) is preferably selected fromthe group consisting of a compound of formula (I-X) or pharmaceuticallyacceptable salt thereof; and a compound of formula (I-Y) orpharmaceutically acceptable salt thereof); wherein the compound offormula (I) or pharmaceutically acceptable salt thereof is present in anamount in the range of from about 1 mg to about 1000 mg, or any amountor range therein (preferably in an amount in the range of from about 1mg to about 500 mg, or any amount or range therein, more preferably inan amount in the range of from about 10 mg to about 300 mg, or anyamount or range therein); and

and (c) glyburide; wherein the glyburide is present in an amount in therange of from about 1.0 mg to about 20 mg, preferably from about 2.5 mgto about 20 mg, or any amount or range therein.

In an embodiment, the present invention is directed to a pharmaceuticalcomposition comprising (a) metformin hydrochloride; (b) a compound offormula (I) or pharmaceutically acceptable salt thereof selected fromthe group consisting of a compound of formula (I-X) or pharmaceuticallyacceptable salt thereof; and a compound of formula (I-Y) orpharmaceutically acceptable salt thereof; and one or morepharmaceutically acceptable excipients. The pharmaceutically acceptableexcipients, include but are not limited to, disintegrants, binders,diluents, lubricants, stabilizers, antioxidants, surfactants, colorants,plasticizers, coatings and the like. More particularly, suitablepharmaceutical excipients comprise one or more of the following: (i)diluents such as lactose, microcrystalline cellulose, dicalciumphosphate, starch and the like; (ii) binders such aspolyvinylpyrrolidone (such as POVIDONE), methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose (such as METHOCEL™ E-5), andthe like; (iii) disintegrants such as sodium starch glycolate,croscamellose sodium, crospovidone and the like; (iv) wetting agentssuch as surfactants, such as sodium lauryl stearate, polysorbate 20, andthe like; (v) lubricants such as magnesium stearate, sodium stearylfumarate, talc, and the like; (vi) flow promoters or glidants such ascolloidal silicon dioxide, talc and the like; and other excipients knownto be useful in the preparation of pharmaceutical compositions.Additional suitable pharmaceutical excipients and their properties maybe found in texts such as Handbook of Pharmaceutical Excipients, Editedby R. C. Rowe, P. J. Sheskey & P. J. Weller, Fourth Edition (Publishedby Pharmaceutical Press, a Division of Royal Pharmaceutical Society ofGreat Britain). In another embodiment, the present invention is directedto a pharmaceutical composition as described above, further comprising asulfonylurea or pharmaceutically acceptable salt thereof.

Fillers or diluents for use in the pharmaceutical compositions of thepresent invention include fillers or diluents typically used in theformulation of pharmaceuticals. Examples of fillers or diluents for usein accordance with the present invention include but are not limited tosugars such as lactose, dextrose, glucose, sucrose, cellulose, starchesand carbohydrate derivatives, polysaccharides (including dextrates andmaltodextrin), polyols (including mannitol, xylitol, and sorbitol),cyclodextrins, calcium carbonates, magnesium carbonates,microcrystalline cellulose, combinations thereof, and the like.

Binders for use in the pharmaceutical compositions of the presentinvention include binders commonly used in the formulation ofpharmaceuticals. Examples of binders for use in accordance with thepresent invention include but are not limited to cellulose derivatives(including hydroxypropyl cellulose, hydroxypropyl methylcellulose,methylcellulose, and sodium carboxymethyl cellulose), glycol, sucrose,dextrose, corn syrup, polysaccharides (including acacia, targacanth,guar, alginates and starch), corn starch, pregelatinized starch,modified corn starch, gelatin, polyvinylpyrrolidone, polyethylene,polyethylene glycol, combinations thereof and the like.

Disintegrants for use in the pharmaceutical compositions of the presentinvention include disintegrants commonly used in the formulation ofpharmaceuticals. Examples of disintegrants for use in accordance withthe present invention include but are not limited to starches, andcrosslinked starches, celluloses and polymers, combinations thereof andthe like. Representative disintegrants include microcrystallinecellulose, croscarmellose sodium, alginic acid, sodium alginate,crosprovidone, cellulose, agar and related gums, sodium starchglycolate, corn starch, potato starch, sodium starch glycolate, VeegumHV, methylcellulose, agar, bentonite, sodium carboxymethylcellulose,calcium carboxymethylcellulose, carboxymethylcellulose, alginic acid,guar gum combinations thereof, and the like.

Lubricants, glidants or anti-tacking agents for use in thepharmaceutical compositions of the present invention include lubricants,glidants and anti-tacking agents commonly used in the formulation ofpharmaceuticals. Examples for use in accordance with the presentinvention include but are not limited to magnesium carbonate, magnesiumlaurylsulphate, calcium silicate, talc, fumed silicon dioxide,combinations thereof, and the like. Other useful lubricants include butare not limited to magnesium stearate, calcium stearate, stearic acid,sodium stearyl fumarate, polyethylene glycol, sodium lauryl sulphate,magnesium lauryl sulphate, sodium benzoate, colloidal silicon dioxide,magnesium oxide, magnesium silicate, mineral oil, hydrogenated vegetableoils, waxes, glyceryl behenate, polyethylene glycol, and combinationsthereof, and the like.

Surfactants for use in the pharmaceutical compositions of the presentinvention include surfactants commonly used in the formulation ofpharmaceuticals. Examples of surfactants for use in accordance with thepresent invention include but are not limited to ionic- and nonionicsurfactants or wetting agents commonly used in the formulation ofpharmaceuticals, such as ethoxylated castor oil, polyglycolyzedglycerides, acetylated monoglycerides, sorbitan fatty acid esters,poloxamers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylenederivatives, monoglycerides or ethoxylated derivatives thereof,diglycerides or polyoxyethylene derivatives thereof, sodium docusate,sodium laurylsulfate, cholic acid or derivatives thereof, lecithins,phospholipids, combinations thereof, and the like.

Other polymers commonly used as excipients in pharmaceuticalcompositions include, but are not limited to, methylcellulose (MC),ethylcellulose (EC), hydroxyethylcellulose (HEC), methylhydroxyethylcellulose (MHEC), hydroxypropyl cellulose (HPC),hydroxypropyl methylcellulose (HPMC), sodium carboxymethylcellulose(NaCMC), and the like.

The pharmaceutical compositions can further comprise antioxidants andchelating agents. For example, the pharmaceutical formulations cancomprise butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT),propyl gallate (PG), sodium metabisulfite, ascorbyl palmitate, potassiummetabisulfite, disodium EDTA (ethylenediamine tetraacetic acid; alsoknown as disodium edentate), EDTA, tartaric acid, citric acid, citricacid monohydrate, and sodium sulfite.

The pharmaceutical compositions may further optionally comprise one ormore flow regulators (or glidants). Flow regulators may be present inpowders or granules and are admixed in order to increase theirflowability of the composition during manufacture, particularly in thepreparation of tablets produced by pressing powders or granules. Flowregulators which can be employed include, but are not limited to, highlydisperse silicon dioxide (Aerosil) or dried starch.

One skilled in the art will readily recognize that the appropriatepharmaceutically acceptable excipients are selected such that they arecompatible with other excipients and do not bind with the drugcompound(s) (active ingredient(s)) or cause drug degradation.

Tablet compositions may further optionally comprise a coating. Suitablecoatings include, but are not limited to, film-forming polymers, suchas, for example, those from the group of the cellulose derivatives,dextrins, starches, natural gums, such as, for example, gum arabic,xanthans, alginates, polyvinyl alcohol, polymethacrylates andderivatives thereof, such as, for example, Eudragit®; which may beapplied to the tablet as solutions or suspensions by means of thevarious pharmaceutical conventional methods, such as, for example, filmcoating. The coating is typically applied as a solutions/suspensionswhich, in addition to any film-forming polymer present, may furthercomprise one or more adjuvants, such as hydrophilisers, plasticisers,surfactants, dyes and white pigments, such as, for example, titaniumdioxide.

In certain embodiments of the present invention, the pharmaceuticalcomposition preferably comprising between about 5% and about 50% byweight of diluents (relative to the total weight of the composition orcomposition layer), more preferably between about 5% and about 25% byweight diluent, more preferably still about 7% diluent.

In additional embodiments of the present invention, the pharmaceuticalcomposition preferably comprising between about 1% and about 10% byweight of binder (relative to the total weight of the composition orcomposition layer), more preferably between about 3% and about 5% byweight binder, more preferably still about 4% binder.

In additional embodiments of the present invention, the pharmaceuticalcomposition preferably comprising between about 1% and about 10% byweight of disintegrant (relative to the total weight of the compositionor composition layer), more preferably between about 2% and about 5% byweight disintegrant, more preferably still about 3% disintegrant.

In additional embodiments of the present invention, the pharmaceuticalcomposition preferably comprising between about 0% and about 5% byweight of wetting agent (relative to the total weight of the compositionor composition layer), more preferably between about 0.1% and about 2%by weight wetting agent, more preferably still about 0.3% wetting agent.

In additional embodiments of the present invention, the pharmaceuticalcomposition preferably comprising between about 0% and about 3% byweight of lubricant (relative to the total weight of the composition orcomposition layer), more preferably between about 0.1% and about 2% byweight lubricant, more preferably still about 0.5% lubricant.

DEFINITIONS

The term “halogen atom” or “halo” means chlorine, bromine, fluorine andiodine, and chlorine and fluorine are preferable.

The term “alkyl group” means a straight or branched saturated monovalenthydrocarbon chain having 1 to 12 carbon atoms. The straight chain orbranched chain alkyl group having 1 to 6 carbon atoms is preferable, andthe straight chain or branched chain alkyl group having 1 to 4 carbonatoms is more preferable. Examples thereof are methyl group, ethylgroup, propyl group, isopropyl group, butyl group, t-butyl group,isobutyl group, pentyl group, hexyl group, isohexyl group, heptyl group,4,4-dimethylpentyl group, octyl group, 2,2,4-trimethylpentyl group,nonyl group, decyl group, and various branched chain isomers thereof.Further, the alkyl group may optionally and independently be substitutedby 1 to 4 substituents as listed below, if necessary.

The term “alkylene group” or “alkylene” means a straight or brancheddivalent saturated hydrocarbon chain having 1 to 12 carbon atoms. Thestraight chain or branched chain alkylene group having 1 to 6 carbonatoms is preferable, and the straight chain or branched chain alkylenegroup having 1 to 4 carbon atoms is more preferable. Examples thereofare methylene group, ethylene group, propylene group, trimethylenegroup, etc. If necessary, the alkylene group may optionally besubstituted in the same manner as the above-mentioned “alkyl group”.Where alkylene groups as defined above attach at two different carbonatoms of the benzene ring, they form an annelated five, six or sevenmembered carbocycle together with the carbon atoms to which they areattached, and may optionally be substituted by one or more substituentsdefined below.

The term “alkenyl group” means a straight or branched monovalenthydrocarbon chain having 2 to 12 carbon atoms and having at least onedouble bond. Preferable alkenyl group is a straight chain or branchedchain alkenyl group having 2 to 6 carbon atoms, and the straight chainor branched chain alkenyl group having 2 to 4 carbon atoms is morepreferable. Examples thereof are vinyl group, 2-propenyl group,3-butenyl group, 2-butenyl group, 4-pentenyl group, 3-pentenyl group,2-hexenyl group, 3-hexenyl group, 2-heptenyl group, 3-heptenyl group,4-heptenyl group, 3-octenyl group, 3-nonenyl group, 4-decenyl group,3-undecenyl group, 4-dodecenyl group, 4,8,12-tetradecatrienyl group,etc. The alkenyl group may optionally and independently be substitutedby 1 to 4 substituents as mentioned below, if necessary.

The term “alkenylene group” means a straight or branched divalenthydrocarbon chain having 2 to 12 carbon atoms and having at least onedouble bond. The straight chain or branched chain alkenylene grouphaving 2 to 6 carbon atoms is preferable, and the straight chain orbranched chain alkenylene group having 2 to 4 carbon atoms is morepreferable. Examples thereof are vinylene group, propenylene group,butadienylene group, etc. If necessary, the alkylene group mayoptionally be substituted by 1 to 4 substituents as mentioned below, ifnecessary. Where alkenylene groups as defined above attach at twodifferent carbon atoms of the benzene ring, they form an annelated five,six or seven membered carbocycle (e.g., a fused benzene ring) togetherwith the carbon atoms to which they are attached, and may optionally besubstituted by one or more substituents defined below.

The term “alkynyl group” means a straight or branched monovalenthydrocarbon chain having at least one triple bond. The preferablealkynyl group is a straight chain or branched chain alkynyl group having2 to 6 carbon atoms, and the straight chain or branched chain alkynylgroup having 2 to 4 carbon atoms is more preferable. Examples thereofare 2-propynyl group, 3-butynyl group, 2-butynyl group, 4-pentynylgroup, 3-pentynyl group, 2-hexynyl group, 3-hexynyl group, 2-heptynylgroup, 3-heptynyl group, 4-heptynyl group, 3-octynyl group, 3-nonynylgroup, 4-decynyl group, 3-undecynyl group, 4-dodecynyl group, etc. Thealkynyl group may optionally and independently be substituted by 1 to 4substituents as mentioned below, if necessary.

The term “cycloalkyl group” means a monocyclic or bicyclic monovalentsaturated hydrocarbon ring having 3 to 12 carbon atoms, and themonocyclic saturated hydrocarbon group having 3 to 7 carbon atoms ismore preferable. Examples thereof are a monocyclic alkyl group and abicyclic alkyl group such as cyclopropyl group, cyclobutyl group,cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctylgroup, cyclodecyl group, etc. These groups may optionally andindependently be substituted by 1 to 4 substituents as mentioned below,if necessary. The cycloalkyl group may optionally be condensed with asaturated hydrocarbon ring or an unsaturated hydrocarbon ring (saidsaturated hydrocarbon ring and unsaturated hydrocarbon ring mayoptionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO orSO₂ within the ring, if necessary), and the condensed saturatedhydrocarbon ring and the condensed unsaturated hydrocarbon ring may beoptionally and independently be substituted by 1 to 4 substituents asmentioned below.

The term “cycloalkylidene group” means a monocyclic or bicyclic divalentsaturated hydrocarbon ring having 3 to 12 carbon atoms, and themonocyclic saturated hydrocarbon group having 3 to 6 carbon atoms ispreferable. Examples thereof are a monocyclic alkylidene group and abicyclic alkylidene group such as cyclopropylidene group,cyclobutylidene group, cyclopentylidine group, cyclohexylidene group,etc. These groups may optionally and independently be substituted by 1to 4 substituents as mentioned below, if necessary. Besides, thecycloalkylidene group may optionally be condensed with a saturatedhydrocarbon ring or an unsaturated hydrocarbon ring (said saturatedhydrocarbon ring and unsaturated hydrocarbon ring may optionally containan oxygen atom, a nitrogen atom, a sulfur atom, SO or SO₂ within thering, if necessary), and the condensed saturated hydrocarbon ring andthe unsaturated hydrocarbon ring may be optionally and independently besubstituted by 1 to 4 substituents as mentioned below.

The term “cycloalkenyl group” means a monocyclic or bicyclic monovalentunsaturated hydrocarbon ring having 4 to 12 carbon atoms and having atleast one double bond. The preferable cycloalkenyl group is a monocyclicunsaturated hydrocarbon group having 4 to 7 carbon atoms. Examplesthereof are monocyclic alkenyl groups such as cyclopentenyl group,cyclopentadienyl group, cyclohexenyl group, etc. These groups mayoptionally and independently be substituted by 1 to 4 substituents asmentioned below, if necessary. Besides, the cycloalkenyl group mayoptionally be condensed with a saturated hydrocarbon ring or anunsaturated hydrocarbon ring (said saturated hydrocarbon ring andunsaturated hydrocarbon ring may optionally contain an oxygen atom, anitrogen atom, a sulfur atom, SO or SO₂ within the ring, if necessary),and the condensed saturated hydrocarbon ring and the unsaturatedhydrocarbon ring may be optionally and independently be substituted by 1to 4 substituents as mentioned below.

The term “cycloalkynyl group” means a monocyclic or bicyclic unsaturatedhydrocarbon ring having 6 to 12 carbon atoms, and having at least onetriple bond. The preferable cycloalkynyl group is a monocyclicunsaturated hydrocarbon group having 6 to 8 carbon atoms. Examplesthereof are monocyclic alkynyl groups such as cyclooctynyl group,cyclodecynyl group. These groups may optionally be substituted by 1 to 4substituents as mentioned below, if necessary. Besides, the cycloalkynylgroup may optionally and independently be condensed with a saturatedhydrocarbon ring or an unsaturated hydrocarbon ring (said saturatedhydrocarbon ring and unsaturated hydrocarbon ring may optionally containan oxygen atom, a nitrogen atom, a sulfur atom, SO or SO₂ within thering, if necessary), and the condensed saturated hydrocarbon ring or theunsaturated hydrocarbon ring may be optionally and independently besubstituted by 1 to 4 substituents as mentioned below.

The term “aryl group” means a monocyclic or bicyclic monovalent aromatichydrocarbon group having 6 to 10 carbon atoms. Examples thereof arephenyl group, naphthyl group (including 1-naphthyl group and 2-naphthylgroup). These groups may optionally and independently be substituted by1 to 4 substituents as mentioned below, if necessary. Besides, the arylgroup may optionally be condensed with a saturated hydrocarbon ring oran unsaturated hydrocarbon ring (said saturated hydrocarbon ring andunsaturated hydrocarbon ring may optionally contain an oxygen atom, anitrogen atom, a sulfur atom, SO or SO₂ within the ring, if necessary),and the condensed saturated hydrocarbon ring or the unsaturatedhydrocarbon ring may be optionally and independently be substituted by 1to 4 substituents as mentioned below.

The term “unsaturated monocyclic heterocyclic ring” means an unsaturatedhydrocarbon ring containing 1-4 heteroatoms independently selected froma nitrogen atom, an oxygen atom and a sulfur atom, and the preferableone is a 4- to 7-membered saturated or unsaturated hydrocarbon ringcontaining 1-4 heteroatoms independently selected from a nitrogen atom,an oxygen atom and a sulfur atom. Examples thereof are pyridine,pyrimidine, pyrazine, furan, thiophene, pyrrole, imidazole, pyrazole,oxazole, isoxazole, 4,5-dihydrooxazole, thiazole, isothiazole,thiadiazole, triazole, tetrazole, etc. Among them, pyridine, pyrimidine,pyrazine, furan, thiophene, pyrrole, imidazole, oxazole, and thiazolecan be preferably used. The “unsaturated monocyclic heterocyclic ring”may optionally and independently be substituted by 1-4 substituents asmentioned below, if necessary.

The term “unsaturated fused heterobicyclic ring” means hydrocarbon ringcomprised of a saturated or a unsaturated hydrocarbon ring condensedwith the above mentioned unsaturated monocyclic heterocyclic ring wheresaid saturated hydrocarbon ring and said unsaturated hydrocarbon ringmay optionally contain an oxygen atom, a nitrogen atom, a sulfur atom,SO, or SO₂ within the ring, if necessary. The “unsaturated fusedheterobicyclic ring” includes, for example, benzothiophene, indole,tetrahydrobenzothiophene, benzofuran, isoquinoline, thienothiophene,thienopyridine, quinoline, indoline, isoindoline, benzothiazole,benzoxazole, indazole, dihydroisoquinoline, etc. Further, the“heterocyclic ring” also includes possible N- or S-oxides thereof.

The term “heterocyclyl” means a monovalent group of the above-mentionedunsaturated monocyclic heterocyclic ring or unsaturated fusedheterobicyclic ring and a monovalent group of the saturated version ofthe above-mentioned unsaturated monocyclic heterocyclic or unsaturatedfused heterobicyclic ring. If necessary, the heterocyclyl may optionallyand independently be substituted by 1 to 4 substituents as mentionedbelow.

The term “alkanoyl group” means a formyl group and ones formed bybinding an “alkyl group” to a carbonyl group.

The term “alkoxy group” means ones formed by binding an “alkyl group” toan oxygen atom.

The substituent for the above each group includes, for example, ahalogen atom (e.g., fluorine, chlorine, bromine, iodine), a nitro group,a cyano group, an oxo group, a hydroxy group, a mercapto group, acarboxyl group, a sulfo group, an alkyl group, an alkenyl group, analkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, acycloalkenyl group, a cycloalkynyl group, an aryl group, a heterocyclylgroup, an alkoxy group, an alkenyloxy group, an alkynyloxy group, acycloalkyloxy group, a cycloalkenyloxy group, a cycloalkynyloxy group,an aryloxy group, a heterocyclyloxy group, an alkanoyl group, analkenylcarbonyl group, an alkynylcarbonyl group, a cycloalkylcarbonylgroup, a cycloalkenylcarbonyl group, a cycloalkynylcarbonyl group, anarylcarbonyl group, a heterocyclylcarbonyl group, an alkoxycarbonylgroup, an alkenyloxycarbonyl group, an alkynyloxycarbonyl group, acycloalkyloxycarbonyl group, a cycloalkenyloxycarbonyl group, acycloalkynyloxycarbonyl group, an aryloxycarbonyl group, aheterocyclyloxycarbonyl group, an alkanoyloxy group, analkenylcarbonyloxy group, an alkynylcarbonyloxy group, acycloalkylcarbonyloxy group, a cycloalkenylcarbonyloxy group, acycloalkynylcarbonyloxy group, an arylcarbonyloxy group, aheterocyclylcarbonyloxy group, an alkylthio group, an alkenylthio group,an alkynylthio group, a cycloalkylthio group, a cycloalkenylthio group,a cycloalkynylthio group, an arylthio group, a heterocyclylthio group,an amino group, a mono- or di-alkylamino group, a mono- ordi-alkanoylamino group, a mono- or di-alkoxycarbonylamino group, a mono-or di-arylcarbonylamino group, an alkylsulfinylamino group, analkylsulfonylamino group, an arylsulfinylamino group, anarylsulfonylamino group, a carbamoyl group, a mono- or di-alkylcarbamoylgroup, a mono- or di-arylcarbamoyl group, an alkylsulfinyl group, analkenylsulfinyl group, an alkynylsulfinyl group, a cycloalkylsulfinylgroup, a cycloalkenylsulfinyl group, a cycloalkynylsulfinyl group, anarylsulfinyl group, a heterocyclylsulfinyl group, an alkylsulfonylgroup, an alkenylsulfonyl group, an alkynylsulfonyl group, acycloalkylsulfonyl group, a cycloalkenylsulfonyl group, acycloalkynylsulfonyl group, an arylsulfonyl group, and aheterocyclylsulfonyl group. Each group as mentioned above may optionallybe substituted by these substituents.

Further, the terms such as a haloalkyl group, a halo-lower alkyl group,a haloalkoxy group, a halo-lower alkoxy group, a halophenyl group, or ahaloheterocyclyl group mean an alkyl group, a lower alkyl group, analkoxy group, a lower alkoxy group, a phenyl group or a heterocyclylgroup (hereinafter, referred to as an alkyl group, etc.) beingsubstituted by one or more halogen atoms, respectively. Preferable onesare an alkyl group, etc. being substituted by 1 to 7 halogen atoms, andmore preferable ones are an alkyl group, etc. being substituted by 1 to5 halogen atoms. Similarly, the terms such as a hydroxyalkyl group, ahydroxy-lower alkyl group, a hydroxyalkoxy group, a hydroxy-lower alkoxygroup and a hydroxyphenyl group mean an alkyl group, etc., beingsubstituted by one or more hydroxy groups. Preferable ones are an alkylgroup, etc., being substituted by 1 to 4 hydroxy groups, and morepreferable ones are an alkyl group, etc., being substituted by 1 to 2hydroxy groups. Further, the terms such as an alkoxyalkyl group, a loweralkoxyalkyl group, an alkoxy-lower alkyl group, a lower alkoxy-loweralkyl group, an alkoxyalkoxy group, a lower alkoxyalkoxy group, analkoxy-lower alkoxy group, a lower alkoxy-lower alkoxy group, analkoxyphenyl group, and a lower alkoxyphenyl group means an alkyl group,etc., being substituted by one or more alkoxy groups. Preferable onesare an alkyl group, etc., being substituted by 1 to 4 alkoxy groups, andmore preferable ones are an alkyl group, etc., being substituted by 1 to2 alkoxy groups.

The terms “arylakyl” and “arylalkoxy” as used alone or as part ofanother group refer to alkyl and alkoxy groups as described above havingan aryl substituent.

The term “lower” used in the definitions for the formulae in the presentspecification means a straight or branched carbon chain having 1 to 6carbon atoms, unless defined otherwise. More preferably, it means astraight or branched carbon chain having 1 to 4 carbon atoms.

Examples of the optionally substituted unsaturated monocyclicheterocyclic ring of the present invention include an unsaturatedmonocyclic heterocyclic ring which may optionally be substituted by 1-5substituents selected from the group consisting of a halogen atom, anitro group, a cyano group, an oxo group, a hydroxyl group, a mercaptogroup, a carboxyl group, a sulfo group, an alkyl group, an alkenylgroup, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethylgroup, a cycloalkenyl group, a cycloalkynyl group, an aryl group, aheterocyclyl group, an alkoxy group, an alkenyloxy group, an alkynyloxygroup, a cycloalkyloxy group, a cycloalkenyloxy group, a cycloalkynyloxygroup, an aryloxy group, a heterocyclyloxy group, an alkanoyl group, analkenylcarbonyl group, an alkynylcarbonyl group, a cycloalkylcarbonylgroup, a cycloalkenylcarbonyl group, a cycloalkynylcarbonyl group, anarylcarbonyl group, a heterocyclylcarbonyl group, an alkoxycarbonylgroup, an alkenyloxycarbonyl group, an alkynyloxycarbonyl group, acycloalkyloxycarbonyl group, a cycloalkenyloxycarbonyl group, acycloalkynyloxycarbonyl group, an aryloxycarbonyl group, aheterocyclyloxycarbonyl group, an alkanoyloxy group, analkenylcarbonyloxy group, an alkynylcarbonyloxy group, acycloalkylcarbonyloxy group, a cycloalkenylcarbonyloxy group, acycloalkynylcarbonyloxy group, an arylcarbonyloxy group, aheterocyclylcarbonyloxy group, an alkylthio group, an alkenylthio group,an alkynylthio group, a cycloalkylthio group, a cycloalkenylthio group,a cycloalkynylthio group, an arylthio group, a heterocyclylthio group,an amino group, a mono- or di-alkylamino group, a mono- ordi-alkanoylamino group, a mono- or di-alkoxycarbonylamino group, a mono-or di-arylcarbonylamino group, an alkylsulfinylamino group, analkylsulfonylamino group, an arylsulfinylamino group, anarylsulfonylamino group, a carbamoyl group, a mono- or di-alkylcarbamoylgroup, a mono- or di-arylcarbamoyl group, an alkylsulfinyl group, analkenylsulfinyl group, an alkynylsulfinyl group, a cycloalkylsulfinylgroup, a cycloalkenylsulfinyl group, a cycloalkynylsulfinyl group, anarylsulfinyl group, a heterocyclylsulfinyl group, an alkylsulfonylgroup, an alkenylsulfonyl group, an alkynylsulfonyl group, acycloalkylsulfonyl group, a cycloalkenylsulfonyl group, acycloalkynylsulfonyl group, an arylsulfonyl group, and aheterocyclylsulfonyl group wherein each substituent may optionally befurther substituted by these substituents.

Examples of the optionally substituted unsaturated fused heterobicyclicring of the present invention include an unsaturated fusedheterobicyclic ring which may optionally be substituted by 1-5substituents selected from the group consisting of a halogen atom, anitro group, a cyano group, an oxo group, a hydroxy group, a mercaptogroup, a carboxyl group, a sulfo group, an alkyl group, an alkenylgroup, an alkynyl group, a cycloalkyl group, a cycloalkylidene-methylgroup, a cycloalkenyl group, a cycloalkynyl group, an aryl group, aheterocyclyl group, an alkoxy group, an alkenyloxy group, an alkynyloxygroup, a cycloalkyloxy group, a cycloalkenyloxy group, a cycloalkynyloxygroup, an aryloxy group, a heterocyclyloxy group, an alkanoyl group, analkenylcarbonyl group, an alkynylcarbonyl group, a cycloalkylcarbonylgroup, a cycloalkenyl-carbonyl group, a cycloalkynyl-carbonyl group, anarylcarbonyl group, a heterocyclylcarbonyl group, an alkoxycarbonylgroup, an alkenyloxycarbonyl group, an alkynyloxy-carbonyl group, acycloalkyloxycarbonyl group, a cycloalkenyloxy-carbonyl group, acycloalkynyloxycarbonyl group, an aryloxycarbonyl group, aheterocyclyloxycarbonyl group, an alkanoyloxy group, analkenylcarbonyloxy group, an alkynylcarbonyloxy group, acyclo-alkylcarbonyloxy group, a cycloalkenylcarbonyloxy group, acyclo-alkynylcarbonyloxy group, an arylcarbonyloxy group, aheterocyclyl-carbonyloxy group, an alkylthio group, an alkenylthiogroup, an alkynylthio group, a cycloalkylthio group, a cycloalkenylthiogroup, a cycloalkynylthio group, an arylthio group, a heterocyclylthiogroup, an amino group, a mono- or di-alkylamino group, a mono- ordi-alkanoyl-amino group, a mono- or di-alkoxycarbonylamino group, amono- or di-arylcarbonylamino group, an alkylsulfinylamino group, analkyl-sulfonylamino group, an arylsulfinylamino group, anarylsulfonylamino group, a carbamoyl group, a mono- or di-alkylcarbamoylgroup, a mono- or di-arylcarbamoyl group, an alkylsulfinyl group, analkenylsulfinyl group, an alkynylsulfinyl group, a cycloalkylsulfinylgroup, a cyclo-alkenylsulfinyl group, a cycloalkynylsulfinyl group, anarylsulfinyl group, a heterocyclylsulfinyl group, an alkylsulfonylgroup, an alkenylsulfonyl group, an alkynylsulfonyl group, acycloalkylsulfonyl group, a cyclo-alkenylsulfonyl group, acycloalkynylsulfonyl group, an arylsulfonyl group, and aheterocyclylsulfonyl group, wherein each substituent may optionally befurther substituted by these substituents.

Examples of the optionally substituted benzene ring of the presentinvention include a benzene ring which may optionally be substituted by1-5 substituents selected from the group consisting of a halogen atom, anitro group, a cyano group, a hydroxy group, a mercapto group, acarboxyl group, a sulfo group, an alkyl group, an alkenyl group, analkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, acycloalkenyl group, a cycloalkynyl group, an aryl group, a heterocyclylgroup, an alkoxy group, an alkenyloxy group, an alkynyloxy group, acycloalkyloxy group, a cycloalkenyloxy group, a cycloalkynyloxy group,an aryloxy group, a heterocyclyloxy group, an alkanoyl group, analkenylcarbonyl group, an alkynylcarbonyl group, a cycloalkylcarbonylgroup, a cycloalkenylcarbonyl group, a cycloalkynylcarbonyl group, anarylcarbonyl group, a heterocyclylcarbonyl group, an alkoxycarbonylgroup, an alkenyloxycarbonyl group, an alkynyloxycarbonyl group, acycloalkyloxycarbonyl group, a cycloalkenyloxycarbonyl group, acycloalkynyloxycarbonyl group, an aryloxycarbonyl group, aheterocyclyloxycarbonyl group, an alkanoyloxy group, analkenylcarbonyloxy group, an alkynylcarbonyloxy group, acycloalkylcarbonyloxy group, a cycloalkenylcarbonyloxy group, acycloalkynylcarbonyloxy group, an arylcarbonyloxy group, aheterocyclylcarbonyloxy group, an alkylthio group, an alkenylthio group,an alkynylthio group, a cycloalkylthio group, a cycloalkenylthio group,a cycloalkynylthio group, an arylthio group, a heterocyclylthio group,an amino group, a mono- or di-alkylamino group, a mono- ordi-alkanoylamino group, a mono- or di-alkoxycarbonylamino group, a mono-or di-arylcarbonylamino group, an alkylsulfinylamino group, analkylsulfonylamino group, an arylsulfinylamino group, anarylsulfonylamino group, a carbamoyl group, a mono- or di-alkylcarbamoylgroup, a mono- or di-arylcarbamoyl group, an alkylsulfinyl group, analkenylsulfinyl group, an alkynylsulfinyl group, a cycloalkylsulfinylgroup, a cycloalkenylsulfinyl group, a cycloalkynylsulfinyl group, anarylsulfinyl group, a heterocyclylsulfinyl group, an alkylsulfonylgroup, an alkenylsulfonyl group, an alkynylsulfonyl group, acycloalkylsulfonyl group, a cycloalkenylsulfonyl group, acycloalkynylsulfonyl group, an arylsulfonyl group, aheterocyclylsulfonyl group, an alkylene group, an alkyleneoxy group, analkylenedioxy group, and an alkenylene group wherein each substituentmay optionally be further substituted by these substituents. Moreover,examples of the optionally substituted benzene ring include a benzenering substituted with an alkylene group to form an annelated carbocycletogether with the carbon atoms to which they are attached, and alsoincludes a benzene ring substituted with an alkenylene group to form anannelated carbocycle such as a fused benzene ring together with thecarbon atoms to which they are attached.

Preferable examples of the optionally substituted unsaturated monocyclicheterocyclic ring include an unsaturated monocyclic heterocyclic ringwhich may optionally be substituted by 1-3 substituents selected fromthe group consisting of a halogen atom, a hydroxy group, an alkoxygroup, an alkyl group, a haloalkyl group, a haloalkoxy group, ahydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxy group, analkenyl group, an alkynyl group, a cycloalkyl group, acycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkyloxygroup, an aryl group, an aryloxy group, an arylalkoxy group, a cyanogroup, a nitro group, an amino group, a mono- or di-alkylamino group, analkanoylamino group, an alkoxycarbonylamino group, a carboxyl group, analkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoylgroup, an alkanoyl group, an alkylsulfonylamino group, anarylsulfonylamino group, an alkylsulfinyl group, an alkylsulfonyl group,an arylsulfonyl group, a heterocyclyl group, and an oxo group.

Preferable examples of the optionally substituted unsaturated fusedheterobicyclic ring include an unsaturated fused heterobicyclic ringwhich may optionally be substituted by 1-3 substituents independentlyselected from the group consisting of a halogen atom, a hydroxy group,an alkoxy group, an alkyl group, a haloalkyl group, a haloalkoxy group,a hydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxy group, analkenyl group, an alkynyl group, a cycloalkyl group, acycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkyloxygroup, an aryl group, an aryloxy group, an arylalkoxy group, a cyanogroup, a nitro group, an amino group, a mono- or di-alkylamino group, analkanoylamino group, an alkoxycarbonylamino group, a carboxyl group, analkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoylgroup, an alkanoyl group, an alkylsulfonylamino group, anarylsulfonylamino group, an alkylsulfinyl group, an alkylsulfonyl group,an arylsulfonyl group, a heterocyclyl group, and an oxo group.

Preferable examples of the optionally substituted benzene ring include abenzene ring which may optionally be substituted by 1-3 substituentsselected from the group consisting of a halogen atom, a hydroxy group,an alkoxy group, an alkyl group, a haloalkyl group, a haloalkoxy group,a hydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxy group, analkenyl group, an alkynyl group, a cycloalkyl group, acycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkyloxygroup, an aryl group, an aryloxy group, an arylalkoxy group, a cyanogroup, a nitro group, an amino group, a mono- or di-alkylamino group, analkanoylamino group, an alkoxycarbonylamino group, a carboxyl group, analkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoylgroup, an alkanoyl group, an alkylsulfonylamino group, anarylsulfonylamino group, an alkylsulfinyl group, an alkylsulfonyl group,an arylsulfonyl group, a heterocyclyl group, an alkylene group, analkyleneoxy group, an alkylenedioxy group, and an alkenylene group.

Preferrably, the optionally substituted unsaturated monocyclicheterocyclic ring is an unsaturated monocyclic heterocyclic ring whichmay optionally be substituted by 1-3 substituents, independentlyselected from the group consisting of a halogen atom, a hydroxy group, acyano group, a nitro group, an alkyl group, an alkenyl group, an alkynylgroup, a cycloalkyl group, a cycloalkylidenemethyl group, an alkoxygroup, an alkanoyl group, an alkylthio group, an alkylsulfonyl group, analkylsulfinyl group, an amino group, a mono- or di-alkylamino group, analkanoylamino group, an alkoxycarbonylamino group, a sulfamoyl group, amono- or di-alkylsulfamoyl group, a carboxyl group, an alkoxycarbonylgroup, a carbamoyl group, a mono- or di-alkylcarbamoyl group, analkylsulfonylamino group, a phenyl group, a phenoxy group, aphenylsulfonylamino group, a phenylsulfonyl group, a heterocyclyl group,and an oxo group;

the optionally substituted unsaturated fused heterobicyclic ring is anunsaturated fused heterobicyclic ring which may optionally besubstituted by 1-3 substituents selected from the group consisting of ahalogen atom, a hydroxy group, a cyano group, a nitro group, an alkylgroup, an alkenyl group, an alkynyl group, a cycloalkyl group, acycloalkylidenemethyl group, an alkoxy group, an alkylthio group, analkylsulfonyl group, an alkylsulfinyl group, an amino group, a mono- ordi-alkylamino group, an alkanoylamino group, an alkoxycarbonylaminogroup, a sulfamoyl group, a mono- or di-alkyl-sulfamoyl group, acarboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono- ordi-alkylcarbamoyl group, an alkanoyl group, an alkylsulfonylamino group,a phenyl group, a phenoxy group, a phenylsulfonylamino group,phenylsulfonyl group, a heterocyclyl group, and an oxo group; and

the optionally substituted benzene ring is a benzene ring which mayoptionally be substituted by 1-3 substituents, independently selectedfrom the group consisting of a halogen atom, a hydroxy group, a cyanogroup, a nitro group, an alkyl group, an alkenyl group, an alkynylgroup, a cycloalkyl group, a cycloalkylidenemethyl group, an alkoxygroup, an alkanoyl group, an alkylthio group, an alkylsulfonyl group, analkylsulfinyl group, an amino group, a mono- or di-alkylamino group, analkanoylamino group, an alkoxycarbonylamino group, a sulfamoyl group, amono- or di-alkylsulfamoyl group, a carboxyl group, an alkoxycarbonylgroup, a carbamoyl group, a mono- or di-alkylcarbamoyl group, analkylsulfonylamino group, a phenyl group, a phenoxy group, aphenylsulfonylamino group, a phenylsulfonyl group, a heterocyclyl group,an alkylene group, and an alkenylene group;

wherein each of the above-mentioned substituents on the unsaturatedmonocyclic heterocyclic ring, the unsaturated fused heterobicyclic ringand the benzene ring may further be substituted by 1-3 substituents,independently selected from the group consisting of a halogen atom, ahydroxy group, a cyano group, an alkyl group, a haloalkyl group, analkoxy group, a haloalkoxy group, an alkanoyl group, an alkylthio group,an alkylsulfonyl group, a mono- or di-alkylamino group, a carboxylgroup, an alkoxycarbonyl group, a phenyl group, an alkyleneoxy group, analkylenedioxy group, an oxo group, a carbamoyl group, and a mono- ordi-alkylcarbamoyl group.

Preferably, the optionally substituted unsaturated monocyclicheterocyclic ring is an unsaturated monocyclic heterocyclic ring whichmay optionally be substituted by 1-3 substituents, independentlyselected from the group consisting of a halogen atom, a cyano group, analkyl group, an alkoxy group, an alkanoyl group, a mono- ordi-alkylamino group, an alkanoylamino group, an alkoxycarbonylaminogroup, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, amono- or di-alkylcarbamoyl group, a phenyl group, a heterocyclyl group,and an oxo group;

the optionally substituted unsaturated fused heterobicyclic ring is anunsaturated fused heterobicyclic ring which may optionally besubstituted by 1-3 substituents independently selected from the groupconsisting of a halogen atom, a cyano group, an alkyl group, an alkoxygroup, an alkanoyl group, a mono- or di-alkylamino group, analkanoylamino group, an alkoxycarbonylamino group, a carboxy group, analkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoylgroup, a phenyl group, a heterocyclyl group, and an oxo group; and

the optionally substituted benzene ring is a benzene ring which mayoptionally be substituted by 1-3 substituents, independently selectedfrom the group consisting of a halogen atom, a cyano group, an alkylgroup, an alkoxy group, an alkanoyl group, a mono- or di-alkylaminogroup, an alkanoylamino group, an alkoxycarbonylamino group, a carboxylgroup, an alkoxycarbonyl group, a carbamoyl group, a mono- ordi-alkylcarbamoyl group, a phenyl group, a heterocyclyl group, analkylene group, and an alkenylene group;

wherein each of the above-mentioned substituents on the unsaturatedmonocyclic heterocyclic ring, the unsaturated fused heterobicyclic ringand the benzene ring may further be substituted by 1-3 substituents,independently selected from the group consisting of a halogen atom, acyano group, an alkyl group, a haloalkyl group, an alkoxy group, ahaloalkoxy group, an alkanoyl group, a mono- or di-alkylamino group, acarboxyl group, a hydroxy group, a phenyl group, an alkylenedioxy group,an alkyleneoxy group, an alkoxycarbonyl group, a carbamoyl group and amono- or di-alkylcarbamoyl group.

In a preferred embodiment of the present invention, in the compound offormula (I),

(1) Ring A is an unsaturated monocyclic heterocyclic ring which mayoptionally be substituted by 1-3 substituents, independently selectedfrom the group consisting of a halogen atom, a hydroxy group, a cyanogroup, a nitro group, an alkyl group, an alkenyl group, an alkynylgroup, a cycloalkyl group, a cycloalkylidenemethyl group, an alkoxygroup, an alkanoyl group, an alkylthio group, an alkylsulfonyl group, analklsulfinyl group, an amino group, a mono- or di-alkylamino group, asulfamoyl group, a mono- or di-alkylsulfamoyl group, a carboxyl group,an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoylgroup, an alkylsulfonylamino group, a phenyl group, a phenoxy group, aphenylsulfonylamino group, a phenylsulfonyl group, a heterocyclyl group,and an oxo group, and

Ring B is an unsaturated monocyclic heterocyclic ring, an unsaturatedfused heterobicyclic ring, or a benzene ring, each of which mayoptionally be substituted by 1-3 substituents, independently selectedfrom the group consisting of a halogen atom, a hydroxy group, a cyanogroup, a nitro group, an alkyl group, an alkenyl group, an alkynylgroup, a cycloalkyl group, a cycloalkylidenemethyl group, an alkoxygroup, an alkanoyl group, an alkylthio group, an alkylsulfonyl group, analkylsulfinyl group, an amino group, a mono- or di-alkylamino group, asulfamoyl group, a mono- or di-alkylsulfamoyl group, a carboxyl group,an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoylgroup, an alkylsulfonylamino group, a phenyl group, a phenoxy group, aphenylsulfonylamino group, a phenylsulfonyl group, a heterocyclyl group,an alkylene group, and an alkenylene group;

(2) Ring A is a benzene ring which may optionally be substituted by 1-3substituents, independently selected from the group consisting of ahalogen atom, a hydroxy group, a cyano group, a nitro group, an alkylgroup, an alkenyl group, an alkynyl group, a cycloalkyl group, acycloalkylidenemethyl group, an alkoxy group, an alkanoyl group, analkylthio group, an alkylsulfonyl group, an alklsulfinyl group, an aminogroup, a mono- or di-alkylamino group, an alkanoylamino group, asulfamoyl group, a mono- or di-alkylsulfamoyl group, a carboxyl group,an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoylgroup, an alkylsulfonylamino group, a phenyl group, a phenoxy group, aphenylsulfonylamino group, a phenylsulfonyl group, a heterocyclyl group,an alkylene group, and an alkenylene group, and

Ring B is an unsaturated monocyclic heterocyclic ring or an unsaturatedfused heterobicyclic ring, each of which may optionally be substitutedby 1-3 substituents, independently selected from the group consisting ofa halogen atom, a hydroxy group, a cyano group, a nitro group, an alkylgroup, an alkenyl group, an alkynyl group, a cycloalkyl group, acycloalkylidenemethyl group, an alkoxy group, an alkanoyl group, analkylthio group, an alkylsulfonyl group, an alklsulfinyl group, an aminogroup, a mono- or di-alkylamino group, a sulfamoyl group, a mono- ordi-alkylsulfamoyl group, a carboxyl group, an alkoxycarbonyl group, acarbamoyl group, a mono- or di-alkylcarbamoyl group, analkylsulfonylamino group, a phenyl group, a phenoxy group, aphenylsulfonylamino group, a phenylsulfonyl group, a heterocyclyl group,an alkylene group and an oxo group; or

(3) Ring A is an unsaturated fused heterobicyclic ring which mayoptionally be substituted by 1-3 substituents, independently selectedfrom the group consisting of a halogen atom, a hydroxy group, a cyanogroup, a nitro group, an alkyl group, an alkenyl group, an alkynylgroup, a cycloalkyl group, a cycloalkylidenemethyl group, an alkoxygroup, an alkanoyl group, an alkylthio group, an alkylsulfonyl group, analklsulfinyl group, an amino group, a mono- or di-alkylamino group, asulfamoyl group, a mono- or di-alkylsulfamoyl group, a carboxyl group,an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoylgroup, an alkylsulfonylamino group, a phenyl group, a phenoxy group, aphenylsulfonylamino group, a phenylsulfonyl group, a heterocyclyl group,and an oxo group, and

Ring B is an unsaturated monocyclic heterocyclic ring, an unsaturatedfused heterobicyclic ring, or a benzene ring, each of which mayoptionally be substituted by 1-3 substituents, independently selectedfrom the group consisting of a halogen atom, a hydroxy group, a cyanogroup, a nitro group, an alkyl group, an alkenyl group, an alkynylgroup, a cycloalkyl group, a cycloalkylidenemethyl group, an alkoxygroup, an alkanoyl group, an alkylthio group, an alkylsulfonyl group, analklsulfinyl group, an amino group, a mono- or di-alkylamino group, asulfamoyl group, a mono- or di-alkylsulfamoyl group, a carboxyl group,an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoylgroup, an alkylsulfonylamino group, a phenyl group, a phenoxy group, aphenylsulfonylamino group, a phenylsulfonyl group, a heterocyclyl group,an alkylene group and an oxo group;

wherein each of the above-mentioned substituents on Ring A and Ring Bmay optionally be substituted by 1-3 substituents, independentlyselected from the group consisting of a halogen atom, a cyano group, analkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, analkanoyl group, a mono- or di-alkylamino group, a carboxyl group, ahydroxy group, a phenyl group, an alkylenedioxy group, an alkyleneoxygroup, an alkoxycarbonyl group, a carbamoyl group and a mono- ordi-alkylcarbamoyl group.

In another preferred embodiment of the present invention, in thecompound of formula (I), Ring A and Ring B are

(1) Ring A is an unsaturated monocyclic heterocyclic ring which mayoptionally be substituted by a halogen atom, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group, or an oxo group, and RingB is (a) a benzene ring which may optionally be substituted by a halogenatom; a cyano group; a lower alkyl group; a halo-lower alkyl group; alower alkoxy group; a halo-lower alkoxy group; a mono- or di-loweralkylamino group; a phenyl group optionally substituted by a halogenatom, a cyano group, a lower alkyl group, a halo-lower alkyl group, alower alkoxy group, or a mono- or di-lower alkylamino group; or aheterocyclyl group optionally substituted by a halogen atom, a cyanogroup, a lower alkyl group, a halo-lower alkyl group, a lower alkoxygroup, or a mono- or di-lower alkylamino group; (b) an unsaturatedmonocyclic heterocyclic ring which may optionally be substituted by agroup selected from a halogen atom, cyano group, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group,a mo- or di-lower alkylamino group, a phenyl group which may besubstituted with a halogen atom, cyano group, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group, or a mono- or di-loweralkylamino group; and a heterocyclyl group which may optionally besubstituted with a group selected from a halogen atom, cyano group, alower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or amono- or di-lower alkylamino group; or (c) an unsaturated fusedheterobicyclic ring which may optionally be substituted by a groupselected from a halogen atom, cyano group, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group,a mono- or di-lower alkylamino group, a phenyl group which may besubstituted with a halogen atom, cyano group, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group, or a mono- or di-loweralkylamino group; and a heterocyclyl group which may optionally besubstituted with a group selected from a halogen atom, cyano group, alower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or amono- or di-lower alkylamino group;

(2) Ring A is a benzene ring which may optionally be substituted by ahalogen atom, a lower alkyl group, a halo-lower alkyl group, a loweralkoxy group, a phenyl group, or a lower alkenylene group, and Ring B is(a) an unsaturated monocyclic heterocyclic ring which may optionally besubstituted by a halogen atom; a cyano group; a lower alkyl group; ahalo-lower alkyl group; a phenyl-lower alkyl group; a lower alkoxygroup; a halo-lower alkoxy group; a mono- or di-lower alkylamino group;a phenyl group optionally substituted by a halogen atom, a cyano group,a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, amono- or di-lower alkylamino group, or a carbamoyl group; or aheterocyclyl group optionally substituted by a halogen atom, a cyanogroup, a lower alkyl group, a halo-lower alkyl group, a lower alkoxygroup, a mono- or di-lower alkylamino group or a carbamoyl group; (b) anunsaturated fused heterobicyclic ring which may optionally besubstituted by a group selected from a halogen atom, cyano group, alower alkyl group, a halo-lower alkyl group, a phenyl-lower alkyl group,a lower alkoxy group, a halo-lower alkoxy group, a mo- or di-loweralkylamino group, a phenyl group which may be substituted with a halogenatom, cyano group, a lower alkyl group, a halo-lower alkyl group, alower alkoxy group, or a mono- or di-lower alkylamino group; and aheterocyclyl group which may optionally be substituted with a groupselected from a halogen atom, cyano group, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group, or a mono- or di-loweralkylamino group; or

(3) Ring A is an unsaturated fused heterobicyclic ring which mayoptionally be substituted by a halogen atom, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group, or an oxo group, and RingB is (a) a benzene ring which may optionally be substituted by a groupselected from a halogen atom, cyano group, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group,a mo- or di-lower alkylamino group, a phenyl group which may besubstituted with a halogen atom, cyano group, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group, or a mono- or di-loweralkylamino group; and a heterocyclyl group which may optionally besubstituted with a group selected from a halogen atom, cyano group, alower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or amono- or di-lower alkylamino group; (b) an unsaturated monocyclicheterocyclic ring which may optionally be substituted by a halogen atom;a cyano group; a lower alkyl group; a halo-lower alkyl group; a loweralkoxy group; a halo-lower alkoxy group; a mono- or di-lower alkylaminogroup; a phenyl group optionally substituted by a halogen atom, a cyanogroup, a lower alkyl group, a halo-lower alkyl group, a lower alkoxygroup, or a mono- or di-lower alkylamino group; or a heterocyclyl groupoptionally substituted by a halogen atom, a cyano group, a lower alkylgroup, a halo-lower alkyl group, a lower alkoxy group, or a mono- ordi-lower alkylamino group; or (c) an unsaturated fused heterobicyclicring which may optionally be substituted by a group selected from ahalogen atom, cyano group, a lower alkyl group, a halo-lower alkylgroup, a lower alkoxy group, a halo-lower alkoxy group, a mo- ordi-lower alkylamino group, a phenyl group which may be substituted witha halogen atom, cyano group, a lower alkyl group, a halo-lower alkylgroup, a lower alkoxy group, or a mono- or di-lower alkylamino group;and a heterocyclyl group which may optionally be substituted with agroup selected from a halogen atom, cyano group, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group, or a mono- or di-loweralkylamino group.

In another preferred embodiment, in the compound of formula (I), Y is—CH₂— and is linked at the 3-position of Ring A, with respect to X beingthe 1-position, Ring A is a benzene ring which is substituted by 1-3substituents selected from the group consisting of a lower alkyl group,a halo-lower alkyl group, a halogen atom, a lower alkoxy group, a phenylgroup, and a lower alkenylene group, and Ring B is an unsaturatedmonocyclic heterocyclic ring or an unsaturated fused heterobicyclicring, each of which may be substituted by 1-3 substituents selected fromthe group consisting of a lower alkyl group, a halo-lower alkyl group, aphenyl-lower alkyl group, a halogen atom, a lower alkoxy group, ahalo-lower alkoxy group, a phenyl group, a halophenyl group, acyanophenyl group, a lower alkylphenyl group, a halo-lower alkylphenylgroup, a lower alkoxyphenyl group, a halo-lower alkoxy phenyl group, alower alkylenedioxyphenyl group, a lower alkyleneoxy phenyl group, amono- or di-lower alkylaminophenyl group, a carbamoyl phenyl group, amono- or di-lower alkylcarbamoylphenyl group, a heterocyclyl group, ahaloheterocyclyl group, a cyanoheterocyclyl group, a loweralkylheterocyclyl group, a lower alkoxyheterocyclyl group, a mono- ordi-lower alkylaminoheterocycyclyl group, a carbamoylheterocyclyl group,and a mono- or di-lower alkylcarbamoyl group.

In another more preferable embodiment, in the compound of formula (I), Yis —CH₂— and is linked at the 3-position of Ring A, with respect to Xbeing the 1-position, Ring A is an unsaturated monocyclic heterocyclicring which may be substituted by 1-3 substituents selected from thegroup consisting of a lower alkyl group, a halogen atom, a lower alkoxygroup, and an oxo group, and Ring B is a benzene ring which may besubstituted by 1-3 substituents selected from the group consisting of alower alkyl group, a halo-lower alkyl group, a halogen atom, a loweralkoxy group, a halo-lower alkoxy group, a phenyl group, a halophenylgroup, a cyanophenyl group, a lower alkylphenyl group, a halo-loweralkylphenyl group, a lower alkoxyphenyl group, a heterocyclyl group, ahaloheterocyclyl group, a cyanoheterocyclyl group, a loweralkylheterocyclyl group, and a lower alkoxyheterocyclyl group.

Further, in another preferable embodiment, in the compound of formula(I), Y is —CH₂— and is linked at the 3-position of Ring A, with respectto X being the 1-position, Ring A is an unsaturated monocyclicheterocyclic ring which may be substituted by 1-3 substituents selectedfrom the group consisting of a lower alkyl group, a halogen atom, alower alkoxy group, and an oxo group, and Ring B is an unsaturatedmonocyclic heterocyclic ring or an unsaturated fused heterobicyclicring, each of which may be substituted by 1-3 substituents selected fromthe group consisting of a lower alkyl group, a halo-lower alkyl group, ahalogen atom, a lower alkoxy group, a halo-lower alkoxy group, a phenylgroup, a halophenyl group, a cyanophenyl group, a lower alkylphenylgroup, a halo-lower alkylphenyl group, a lower alkoxyphenyl group, ahalo-lower alkoxyphenyl group, a heterocyclyl group, a haloheterocyclylgroup, a cyanoheterocyclyl group, a lower alkylheterocyclyl group, and alower alkoxyheterocyclyl group. In a more preferable embodiment of thepresent invention, X is a carbon atom and Y is —CH₂—.

Further, in another preferable embodiment, in the compound of formula(I), Ring A and Ring B are

(1) Ring A is a benzene ring which may optionally be substituted by 1-3substituents, independently selected from the group consisting of ahalogen atom, a lower alkyl group optionally substituted by a halogenatom or a lower alkoxy group, a lower alkoxy group optionallysubstituted by a halogen atom or a lower alkoxy group, a cycloalkylgroup, a cycloalkoxy group, a phenyl group, and a lower alkenylenegroup, and

Ring B is an unsaturated monocyclic heterocyclic ring or an unsaturatedfused heterobicyclic ring, each of which may optionally be substitutedby 1-3 substituents, independently selected from the group consisting ofa halogen atom; a lower alkyl group optionally substituted by a halogenatom, a lower alkoxy group or a phenyl group; a lower alkoxy groupoptionally substituted by a halogen atom or a lower alkoxy group; acycloalkyl group; a cycloalkoxy group; a phenyl group optionallysubstituted by a halogen atom, a cyano group, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group,or a carbamoyl group; a heterocyclyl group optionally substituted by ahalogen atom, a cyano group, a lower alkyl group, a halo-lower alkylgroup, a lower alkoxy group, a halo-lower alkoxy group or a carbamoylroup; and an oxo group,

(2) Ring A is an unsaturated monocyclic heterocyclic ring which mayoptionally be substituted by 1-3 substituents, independently selectedfrom the group consisting of a halogen atom, a lower alkyl groupoptionally substituted by a lower alkoxy group, a lower alkoxy groupoptionally substituted by a halogen atom or a lower alkoxy group, acycloalkyl group, a cycloalkoxy group, and an oxo group, and

Ring B is a benzene ring which may optionally be substituted by 1-3substituents, independently selected from the group consisting of ahalogen atom; a lower alkyl group optionally substituted by a halogenatom, a lower alkoxy group or a phenyl group; a lower alkoxy groupoptionally substituted by a halogen atom or a lower alkoxy group; acycloalkyl group; a cycloalkoxy group; a phenyl group optionallysubstituted by a halogen atom, a cyano group, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group or a halo-lower alkoxygroup; a heterocyclyl group optionally substituted by a halogen atom, acyano group, a lower alkyl group, a halo-lower alkyl group, a loweralkoxy group or a halo-lower alkoxy group; a lower alkylene group,

(3) Ring A is an unsaturated monocyclic heterocyclic ring which mayoptionally be substituted by 1-3 substituents, independently selectedfrom the group consisting of a halogen atom, a lower alkyl groupoptionally substituted by a halogen atom or a lower alkoxy group, alower alkoxy group optionally substituted by a halogen atom or a loweralkoxy group, a cycloalkyl group, a cycloalkoxy group, and an oxo group,

Ring B is an unsaturated monocyclic heterocyclic ring or an unsaturatedfused heterobicyclic ring, each of which may optionally be substitutedby 1-3 substituents, independently selected from the group consisting ofa halogen atom; a lower alkyl group optionally substituted by a halogenatom, a lower alkoxy group or a phenyl group; a lower alkoxy groupoptionally substituted by a halogen atom or a lower alkoxy group; acycloalkyl group; a cycloalkoxy group; a phenyl group optionallysubstituted by a halogen atom, a cyano group, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group or a halo-lower alkoxygroup; a heterocyclyl group optionally substituted by a halogen atom, acyano group, a lower alkyl group, a halo-lower alkyl group, a loweralkoxy group or a halo-lower alkoxy group; and an oxo group;

(4) Ring A is an unsaturated fused heterobicyclic ring which mayoptionally be substituted by 1-3 substituents, independently selectedfrom the group consisting of a halogen atom, a lower alkyl groupoptionally substituted by a lower alkoxy group, a lower alkoxy groupoptionally substituted by a halogen atom or a lower alkoxy group, acycloalkyl group, a cycloalkoxy group, and an oxo group,

Ring B is a benzene ring which may optionally be substituted by 1-3substituents, independently selected from the group consisting of ahalogen atom; a lower alkyl group optionally substituted by a halogenatom, a lower alkoxy group or a phenyl group; a lower alkoxy groupoptionally substituted by a halogen atom or a lower alkoxy group; acycloalkyl group; a cycloalkoxy group; a phenyl group optionallysubstituted by a halogen atom, a cyano group, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group or a halo-lower alkoxygroup; a heterocyclyl group optionally substituted by a halogen atom, acyano group, a lower alkyl group, a halo-lower alkyl group, a loweralkoxy group or a halo-lower alkoxy group; and a lower alkylene group,or

(5) Ring A is an unsaturated monocyclic heterocyclic ring which mayoptionally be substituted by 1-3 substituents, independently selectedfrom the group consisting of a halogen atom, a lower alkyl groupoptionally substituted by a lower alkoxy group, a lower alkoxy groupoptionally substituted by a halogen atom or a lower alkoxy group, acycloalkyl group, a cycloalkoxy group, and an oxo group,

Ring B is an unsaturated monocyclic heterocyclic ring or an unsaturatedfused heterobicyclic ring, each of which may optionally be substitutedby 1-3 substituents, independently selected from the group consisting ofa halogen atom; a lower alkyl group optionally substituted by a halogenatom, a lower alkoxy group or a phenyl group; a lower alkoxy groupoptionally substituted by a halogen atom or a lower alkoxy group; acycloalkyl group; a cycloalkoxy group; a phenyl group optionallysubstituted by a halogen atom, a cyano group, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group or a halo-lower alkoxygroup; a heterocyclyl group optionally substituted by a halogen atom, acyano group, a lower alkyl group, a halo-lower alkyl group, a loweralkoxy group or a halo-lower alkoxy group; and an oxo group.

In another preferable embodiment, in the compound of formula (I), Y islinked at the 3-position of Ring A, with respect to X being the1-position, Ring A is a benzene ring which may optionally be substitutedby a halogen atom, a lower alkyl group optionally substituted by ahalogen atom, a lower alkoxy group, or a phenyl group, and Ring B is anunsaturated monocyclic heterocyclic ring or an unsaturated fusedheterobicyclic ring which may optionally be substituted by 1-3substituents, independently selected from the group consisting of ahalogen atom; a lower alkyl group optionally substituted by a halogenatom or a phenyl group; a lower alkoxy group; a phenyl group optionallysubstituted by a halogen atom, a cyano group, a lower alkyl group, ahalo-lower alkyl group, or a lower alkoxy group; a heterocyclyl groupoptionally substituted by a halogen atom, a cyano group, a lower alkylgroup, a halo-lower alkyl group, or a lower alkoxy group; and an oxogroup.

In another more preferable embodiment, in the compound of formula (I), Yis linked at the 3-position of Ring A, with respect to X being the1-position, Ring A is an unsaturated monocyclic heterocyclic ring whichmay optionally be substituted by a substituent selected from a halogenatom, a lower alkyl group, and an oxo group, and Ring B is a benzenering which may optionally be substituted by a substituent selected fromthe group consisting of a halogen atom; a lower alkyl group optionallysubstituted by a halogen atom or a phenyl group; a lower alkoxy group; aphenyl group optionally substituted by a halogen atom, a cyano group, alower alkyl group, a halo-lower alkyl group, or a lower alkoxy group; aheterocyclyl group optionally substituted by a halogen atom, a cyanogroup, a lower alkyl group, a halo-lower alkyl group, or a lower alkoxygroup; and a lower alkylene group.

Preferable examples of unsaturated monocyclic heterocyclic ring includea 5- or 6-membered unsaturated heterocyclic ring containing 1 or 2hetero atoms independently selected from a nitrogen atom, an oxygenatom, and a sulfur atom. More specifically, preferred are furan,thiophene, oxazole, isoxazole, triazole, tetrazole, pyrazole, pyridine,pyrimidine, pyrazine, dihydroisoxazole, dihydropyridine, and thiazole.Preferable unsaturated fused heterobicyclic ring includes a 9- or10-membered unsaturated fused heterocyclic ring containing 1 to 4heteroatoms independently selected from a nitrogen atom, an oxygen atom,and a sulfur atom. More specifically, preferred are indoline,isoindoline, benzothiazole, benzoxazole, indole, indazole, quinoline,isoquinoline, benzothiophene, benzofuran, thienothiophene, anddihydroisoquinoline.

In a more preferred embodiment, in the compound of formula (I), Ring Ais a benzene ring which may optionally be substituted by a substituentselected from the group consisting of a halogen atom, a lower alkylgroup, a halo-lower alkyl group, a lower alkoxy group, and a phenylgroup, and Ring B is a heterocyclic ring selected from the groupconsisting of thiophene, furan, benzofuran, benzothiophene, andbenzothiazole, wherein the heterocyclic ring may optionally besubstituted by a substituent selected from the following group: ahalogen atom, a cyano group, a lower alkyl group, a halo-lower alkylgroup, a phenyl-lower alkyl group, a lower alkoxy group, a halo-loweralkoxy group, a phenyl group, a halophenyl group, a lower alkylphenylgroup, a lower alkoxyphenyl group, a thienyl group, a halothienyl group,a pyridyl group, a halopyridyl group, and a thiazolyl group.

In yet another preferred embodiment, in the compound of formula (I), Yis —CH₂—, Ring A is an unsaturated monocyclic heterocyclic ring or anunsaturated fused heterobicyclic ring selected from the group consistingof thiophene, dihydroisoquinoline, dihydroisoxazole, triazole, pyrazole,dihydropyridine, dihydroindole, indole, indazole, pyridine, pyrimidine,pyrazine, quinoline, and a isoindoline, wherein the heterocyclic ringmay optionally substituted by a substituent selected from the followinggroup: a halogen atom, a lower alkyl group, and an oxo group, and Ring Bis a benzene ring which may optionally be substituted by a substituentselected from the following group: a halogen atom, a lower alkyl group,a halo-lower alkyl group, a lower alkoxy group, and a halo-lower alkoxygroup.

In a further preferred embodiment, in the compound of formula (I), RingA is a benzene ring which is substituted by a halogen atom or a loweralkyl group, and Ring B is thienyl group which is substituted by phenylgroup or a heterocyclyl group in which said phenyl group andheterocyclyl group is substituted by 1-3 substituents selected from ahalogen atom, a cyano group, a lower alkyl group, a halo-lower alkylgroup, a lower alkoxy group, and a halo-lower alkoxy group.

Further, in another aspect of the present invention, preferable examplesof the compound of the formula (I) include a compound wherein Ring A is

wherein R^(1a), R^(2a), R^(3a), R^(1b), R^(2b), and R^(3b) are eachindependently a hydrogen atom, a halogen atom, a hydroxy group, analkoxy group, an alkyl group, a haloalkyl group, a haloalkoxy group, ahydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxy group, analkenyl group, an alkynyl group, a cycloalkyl group, acycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkyloxygroup, a phenyl group, a phenylalkoxy group, a cyano group, a nitrogroup, an amino group, a mono- or di-alkylamino group, an alkanoylaminogroup, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, amono- or di-alkylcarbamoyl group, an alkanoyl group, analkylsulfonylamino group, a phenylsulfonylamino group, an alkylsulfinylgroup, an alkylsulfonyl group, or a phenylsulfonyl group, and

Ring B is

wherein R^(4a) and R^(5a) are each independently a hydrogen atom; ahalogen atom; a hydroxy group; an alkoxy group; an alkyl group; ahaloalkyl group; a haloalkoxy group; a hydroxyalkyl group; analkoxyalkyl group; a phenylalkyl group; an alkoxyalkoxy group; ahydroxyalkoxy group; an alkenyl group; an alkynyl group; a cycloalkylgroup; a cycloalkylidenemethyl group; a cycloalkenyl group; acycloalkyloxy group; a phenyloxy group; a phenylalkoxy group; a cyanogroup; a nitro group; an amino group; a mono- or di-alkylamino group; analkanoylamino group; a carboxyl group; an alkoxycarbonyl group; acarbamoyl group; a mono- or di-alkylcarbamoyl group; an alkanoyl group;an alkylsulfonylamino group; a phenylsulfonylamino group; analkylsulfinyl group; an alkylsulfonyl group; a phenylsulfonyl group; aphenyl group optionally substituted by a halogen atom, a cyano group, analkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, analkylenedioxy group, an alkyleneoxy group, a mono- or di-alkylaminogroup, a carbamoyl group, or a mono- or di-alkylcarbamoyl group; or aheterocyclyl group optionally substituted by a halogen atom, a cyanogroup, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxygroup, a carbamoyl group, or a mono- or di-alkylcarbamoyl group, orR^(4a) and R^(5a) are bonded to each other at the terminals thereof toform an alkylene group; and

R^(4b), R^(5b), R^(4c) and R^(5c) are each independently a hydrogenatom; a halogen atom; a hydroxy group; an alkoxy group; an alkyl group;a haloalkyl group; a haloalkoxy group; a hydroxyalkyl group; analkoxyalkyl group; a phenylalkyl group; an alkoxyalkoxy group; ahydroxyalkoxy group; an alkenyl group; an alkynyl group; a cycloalkylgroup; a cycloalkylidenemethyl group; a cycloalkenyl group; acycloalkyloxy group; a phenyloxy group; a phenylalkoxy group; a cyanogroup; a nitro group; an amino group; a mono- or di-alkylamino group; analkanoylamino group; a carboxyl group; an alkoxycarbonyl group; acarbamoyl group; a mono- or di-alkylcarbamoyl group; an alkanoyl group;an alkylsulfonylamino group; a phenylsulfonylamino group; analkylsulfinyl group; an alkylsulfonyl group; a phenylsulfonyl group; aphenyl group optionally substituted by a halogen atom, a cyano group, analkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, amethylenedioxy group, an ethyleneoxy group, or a mono- or di-alkylaminogroup; or a heterocyclyl group optionally substituted by a halogen atom,a cyano group, an alkyl group, a haloalkyl group, an alkoxy group or ahaloalkoxy group.

More preferred is a compound of formula (I) wherein R^(1a), R^(2a),R^(3a), R^(1b), R^(2b), and R^(3b) are each independently a hydrogenatom, a halogen atom, a lower alkyl group, a halo-lower alkyl group, alower alkoxy group, or a phenyl group;

R^(4a) and R^(5a) are each independently a hydrogen atom; a halogenatom; a lower alkyl group; a halo-lower alkyl group; a phenyl-loweralkyl group; a phenyl group optionally substituted by a halogen atom, acyano group, a lower alkyl group, a halo-lower alkyl group, a loweralkoxy group, a halo-lower alkoxy group, a methylenedioxy group, anethyleneoxy group, a mono- or di-lower alkylamino group, a carbamoylgroup, or a mono- or di-lower alkylcarbamoyl group; or a heterocyclylgroup optionally substituted by a halogen atom, a cyano group, a loweralkyl group, a lower alkoxy group, a carbamoyl group, or a mono- ordi-lower alkylcarbamoyl group, or R^(4a) and R^(5a) are bonded to eachother at the terminals thereof to form a lower alkylene group; and

R^(4b), R^(5b), R^(4c) and R^(5c) are each independently a hydrogenatom, a halogen atom, a lower alkyl group, a halo-lower alkyl group, alower alkoxy group, or a halo-lower alkoxy group.

Further preferred is a compound of formula (I) in which Ring B is a ringof the following structure

wherein R^(4a) is a phenyl group optionally substituted by a halogenatom, a cyano group, a lower alkyl group, a halo-lower alkyl group, alower alkoxy group, a halo-lower alkoxy group, a methylenedioxy group,an ethyleneoxy group, a mono- or di-lower alkylamino group, a carbamoylgroup, or a mono- or di-lower alkylcarbamoyl group; or a heterocyclylgroup optionally substituted by a halogen atom, a cyano group, a loweralkyl group, a lower alkoxy group, a carbamoyl group, or a mono- ordi-lower alkylcarbamoyl group, and

R^(5a) is a hydrogen atom, or

R^(4a) and R^(5a) are bonded to each other at the terminals thereof toform a lower alkylene group.

Further more preferred, is a compound of formula (I) in which Ring A is

wherein R^(1a) is a halogen atom, a lower alkyl group, or a lower alkoxygroup, and R^(2a) and R^(3a) are hydrogen atoms; and Rind B is

wherein R^(4a) is a phenyl group optionally substituted by a substituentselected from the group consisting of a halogen atom, a cyano group, alower alkyl group, a halo-lower alkyl group, a lower alkoxy group, ahalo-lower alkoxy group, a mono- or di-lower alkylamino group, acarbamoyl group, and a mono- or di-lower alkylcarbamoyl group; or aheterocyclyl group optionally substituted by a halogen atom, a cyanogroup, a lower alkyl group, a lower alkoxy group, a carbamoyl group, ora mono- or di-lower alkylcarbamoyl group, and R^(5a) is a hydrogen atom,and Y is —CH₂—.

In more preferable embodiment, in the compound of formula (I), R^(4a) isa phenyl group optionally substituted by a halogen atom, a cyano group,a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, ora halo-lower alkoxy group; or a heterocyclyl group optionallysubstituted by a halogen atom, a cyano group, a lower alkyl group, or alower alkoxy group.

In another embodiment, a preferable compound of formula (I) can berepresented by the following formula (IA):

wherein R^(A) is a halogen atom, a lower alkyl group or a lower alkoxygroup; R^(B) is a phenyl group optionally substituted by 1-3substituents selected from a halogen atom, a cyano group, a lower alkylgroup, a halo-lower alkyl group, a lower alkoxy group, a halo-loweralkoxy group, a methylenedioxy group, an ethyleneoxy group, a mono- ordi-lower alkylamino group, a carbamoyl group, and a mono- or di-loweralkylcarbamoyl group; or a heterocyclyl group optionally substituted by1-3 substituents selected from a halogen atom, a cyano group, a loweralkyl group, a halo-lower alkyl group, a lower alkoxy group, ahalo-lower alkoxy group, a mono- or di-lower alkylamino group, acarbamoyl group, and a mono- or di-lower alkylcarbamoyl group; and R^(C)is hydrogen atom; or R^(B) and R^(C) taken together are a fused benzenering which may be substituted by a halogen atom, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group or a halo-lower alkoxygroup.

In a preferable embodiment, in the compound of formula (I), R^(A) is ahalogen atom or a lower alkyl group, R^(C) is hydrogen atom, and R^(B)is phenyl group substituted by 1-3 substituents selected from a halogenatom, a cyano group, a lower alkyl group, a halo-lower alkyl group, alower alkoxy group, a halo-lower alkoxy group, a methylenedioxy group,an ethyleneoxy group, a mono- or di-lower alkylamino group, a carbamoylgroup, and a mono- or di-lower alkylcarbamoyl group; or a heterocyclylgroup substituted by 1-3 substituents selected from the group consistingof a halogen atom, a cyano group, a lower alkyl group, a halo-loweralkyl group, a lower alkoxy group, a halo-lower alkoxy group, a mono- ordi-lower alkylamino group, a carbamoyl group, and a mono- or di-loweralkylcarbamoyl group. The chemical structure of such compounds arerepresented by the following formula (IA′):

wherein R^(A) is a halogen atom, or a lower alkyl group, Ring C is aphenyl group substituted by 1-3 substituents selected from the groupconsisting of a halogen atom, a cyano group, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group,a methylenedioxy group, an ethyleneoxy group, a mono- or di-loweralkylamino group, a carbamoyl group, and a mono- or di-loweralkylcarbamoyl group; or a heterocyclyl group substituted by 1-3substituents selected from the group consisting of a halogen atom, acyano group, a lower alkyl group, a halo-lower alkyl group, a loweralkoxy group, a halo-lower alkoxy group, a mono- or di-lower alkylaminogroup, a carbamoyl group, and a mono- or di-lower alkylcarbamoyl group.

In a more preferable embodiment, in the compound of formula (I), Ring Cis a phenyl group substituted by 1-3 substituents selected from thegroup consisting of a halogen atom, a cyano group, a lower alkyl group,a halo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxygroup, and a mono- or di-lower alkylamino group; or a heterocyclyl groupsubstituted by a substituent selected from the group consisting of ahalogen atom, a cyano group, a lower alkyl group, a halo-lower alkylgroup, a lower alkoxy group, and a halo-lower alkoxy group.

Among them, a compound of formula (I) in which Ring C is a phenyl groupsubstituted by a halogen atom, a cyano group, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group or a halo-lower alkoxygroup; or a heterocyclyl group substituted by a halogen atom, a cyanogroup, a lower alkyl group, or a lower alkoxy group is preferred.

A preferred heterocyclyl group includes a 5- or 6-membered heterocyclylgroup containing 1 or 2 hetero atoms independently selected from thegroup consisting of a nitrogen atom, an oxygen atom, and a sulfur atom,or a 9- or 10-membered heterocyclyl group containing 1 to 4 hetero atomsindependently selected from the group consisting of a nitrogen atom, anoxygen atom, and a sulfur atom. Specifically, a thienyl group, a pyridylgroup, a pyrimidyl group, a pyrazinyl group, pyrazolyl group, athiazolyl group, a quinolyl group, a tetrazolyl group and an oxazolylgroup are preferred.

In a further preferable embodiment, in the compound of formula (I), RingC is a phenyl group substituted by a halogen atom or a cyano group, or apyridyl group substituted by a halogen atom.

In another embodiment, preferred is a compound of formula (I), in whichRing A is

wherein R^(1a) is a halogen atom, a lower alkyl group, or a lower alkoxygroup, and R^(2a) and R^(3a) are hydrogen atoms; and Ring B is

wherein R^(4b) and R^(5b) are each independently a hydrogen atom, ahalogen atom, a lower alkyl group, a halo-lower alkyl group, a loweralkoxy group, or a halo-lower alkoxy group.

In another aspect of the present invention, preferable examples of thecompound of formula (I), include a compound represented by the followingformula (IB):

wherein R⁸, R⁹ and R¹⁰ are each independently a hydrogen atom, a halogenatom, a hydroxy group, an alkoxy group, an alkyl group, a haloalkylgroup, a haloalkoxy group, a hydroxyalkyl group, an alkoxyalkyl group,an alkoxyalkoxy group, an alkenyl group, an alkynyl group, a cycloalkylgroup, a cycloalkylidenemethyl group, a cycloalkenyl group, acycloalkyloxy group, an aryloxy group, an arylalkoxy group, a cyanogroup, a nitro group, an amino group, a mono- or di-alkylamino group, analkylcarbonylamino group, a carboxyl group, an alkoxycarbonyl group, acarbamoyl group, a mono- or di-alkylcarbamoyl group, an alkanoyl group,an alkylsulfonylamino group, an arylsulfonylamino group, analkylsulfinyl group, an alkylsulfonyl group, or an arylsulfonyl group;and a group represented by:

wherein R^(5a) and R^(7a) are each independently a hydrogen atom, ahalogen atom, a hydroxy group, an alkoxy group, an alkyl group, ahaloalkyl group, a haloalkoxy group, a hydroxyalkyl group, analkoxyalkyl group, an alkoxyalkoxy group, an alkenyl group, an alkynylgroup, a cycloalkyl group, a cycloalkylidenemethyl group, a cycloalkenylgroup, a cycloalkyloxy group, an aryloxy group, an arylalkoxy group, acyano group, a nitro group, an amino group, a mono- or di-alkylaminogroup, an alkylcarbonylamino group, a carboxyl group, an alkoxycarbonylgroup, a carbamoyl group, a mono- or di-alkylcarbamoyl group, analkanoyl group, an alkylsulfonylamino group, an arylsulfonylamino group,an alkylsulfinyl group, an alkylsulfonyl group, or an arylsulfonyl groupand R^(6b) and R^(7b) are each independently a hydrogen atom, a halogenatom, an alkyl group, a haloalkyl group, or an alkoxy group.

Among the compounds represented by the formula (IB), more preferred is acompound in which R⁸, R⁹ and R¹⁰ are each independently a hydrogen atom,a halogen atom, a lower alkyl group, a cycloalkyl group, a hydroxy-loweralkyl group, a halo-lower alkyl group, a lower alkoxy-lower alkyl group,a lower alkoxy group, a cycloalkoxy group, a halo-lower alkoxy group, ora lower alkoxy-lower alkoxy group, and a group represented by:

wherein R^(6a), R^(7a) are each independently a hydrogen atom, a halogenatom, a lower alkyl group, a cycloalkyl group, a hydroxy-lower alkylgroup, a halo-lower alkyl group, a lower alkoxy-lower alkyl group, alower alkoxy group, a cycloalkoxy group, a halo-lower alkoxy group, or alower alkoxy-lower alkoxy group, or a group represented by:

wherein R^(6b) and R^(7b) are each independently a hydrogen atom, ahalogen atom, a lower alkyl group, a halo-lower alkyl group, or a loweralkoxy group.

In another aspect, preferable examples of the compound of formula (I)include a compound represented by the following formula (IC):

wherein Ring B′ is an optionally substituted benzene ring, an optionallysubstituted unsaturated monocyclic heterocyclic ring, or an optionallysubstituted unsaturated fused heterobicyclic ring.

Preferable examples of Ring B′ include a benzene ring and a heterocyclicring, both of which may have a substituent(s) selected from the groupconsisting of a halogen atom; a cyano group; a lower alkyl groupoptionally substituted by a halogen atom; a lower alkoxy groupoptionally substituted by a halogen atom; a lower alkanoyl group; amono- or di-lower alkylamino group; a lower alkoxycarbonyl group; acarbamoyl group; a mono- or di-lower alkylcarbamoyl group; a phenylgroup optionally substituted by a substituent(s) selected from a halogenatom, a cyano group, a lower alkyl group optionally substituted by ahalogen atom, a lower alkoxy group optionally substituted by a halogenatom, a lower alkanoyl group, a mono- or di-lower alkylamino group, alower alkoxycarbonyl group, a carbamoyl group, or a mono- or di-loweralkylcarbamoyl group; a heterocyclyl group optionally substituted by asubstituent(s) selected from a halogen atom, a cyano group, a loweralkyl group optionally substituted by a halogen atom, a lower alkoxygroup optionally substituted by a halogen atom, a lower alkanoyl group,a mono- or di-lower alkylamino group, a lower alkoxycarbonyl group, acarbamoyl group, or a mono- or di-lower alkylcarbamoyl group; analkylene group; and an oxo group.

More preferable examples of Ring B′ include a benzene ring which may besubstituted by a substituent selected from the group consisting of ahalogen atom; a cyano group; a lower alkyl group optionally substitutedby a halogen atom; a lower alkoxy group optionally substituted by ahalogen atom; a mono- or di-lower alkylamino group; a phenyl groupoptionally substituted by a halogen atom, a cyano group, a lower alkylgroup optionally substituted by a halogen atom, a lower alkoxy groupoptionally substituted by a halogen atom; a heterocyclyl groupoptionally substituted by a halogen atom, a cyano group, a lower alkylgroup optionally substituted by a halogen atom, a lower alkoxy groupoptionally substituted by a halogen atom.

Preferred compound of formula (I) may be selected from the groupconsisting of:

-   1-(β-D-glucopyranosyl)-4-chloro-3-(6-ethylbenzo[b]thiophen-2-ylmethyl)benzene;-   1-(β-D-glucopyranosyl)-4-chloro-3-[5-(5-thiazolyl)-2-thienylmethyl]benzene;-   1-(β-D-glucopyranosyl)-4-chloro-3-(5-phenyl-2-thienyl-methyl)benzene;-   1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene;-   1-(β-D-glucopyranosyl)-4-chloro-3-[5-(2-pyrimidinyl)-2-thienylmethyl]benzene;-   1-(β-D-glucopyranosyl)-4-methyl-3-[5-(2-pyrimidinyl)-2-thienylmethyl]benzene;-   1-(β-D-glucopyranosyl)-4-chloro-3-[5-(3-cyanophenyl)-2-thienylmethyl]benzene;-   1-(β-D-glucopyranosyl)-4-chloro-3-[5-(4-cyanophenyl)-2-thienylmethyl]benzene;-   1-(β-D-glucopyranosyl)-4-methyl-3-[5-(6-fluoro-2-pyridyl)-2-thienylmethyl]benzene;-   1-(β-D-glucopyranosyl)-4-chloro-3-[5-(6-fluoro-2-pyridyl)-2-thienylmethyl]benzene;-   1-(β-D-glucopyranosyl)-4-methyl-3-[5-(3-difluoromethyl-phenyl)-2-thienylmethyl]benzene;-   1-(β-D-glucopyranosyl)-4-methyl-3-[5-(3-cyanophenyl)-2-thienylmethyl]benzene;-   1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-cyanophenyl)-2-thienylmethyl]benzene;-   1-(β-D-glucopyranosyl)-4-chloro-3-[5-(6-fluoro-3-pyridyl)-2-thienylmethyl]benzene;-   1-(β-D-glucopyranosyl)-4-fluoro-3-(5-(3-cyanophenyl)-2-thienylmethyl)benzene;

a pharmaceutically acceptable salt thereof; and a prodrug thereof.

Particularly preferred compounds of formula (I) include:

-   1-(β-D-glucopyranosyl)-4-methyl-3-[5-(3-cyano-phenyl)-2-thienylmethyl]benzene,    or a pharmaceutically acceptable salt thereof, or a prodrug thereof;-   1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-cyano-phenyl)-2-thienylmethyl]benzene,    or a pharmaceutically acceptable salt thereof, or a prodrug thereof;-   1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluoro-phenyl)-2-thienylmethyl]benzene,    or a pharmaceutically acceptable salt thereof, or a prodrug thereof;-   1-(β-D-glucopyranosyl)-4-chloro-3-[5-(3-cyano-phenyl)-2-thienylmethyl]benzene,    or a pharmaceutically acceptable salt thereof, or a prodrug thereof;-   1-(β-D-glucopyranosyl)-4-methyl-3-[5-(6-fluoro-2-pyridyl)-2-thienylmethyl]benzene,    or a pharmaceutically acceptable salt thereof, or a prodrug thereof;-   1-(β-D-glucopyranosyl)-4-chloro-3-[5-(6-fluoro-2-pyridyl)-2-thienylmethyl]benzene,    or a pharmaceutically acceptable salt thereof, or a prodrug thereof;-   1-(β-D-glucopyranosyl)-4-chloro-3-[5-(6-fluoro-3-pyridyl)-2-thienylmethyl]benzene,    or a pharmaceutically acceptable salt thereof, or a prodrug thereof;    and-   1-(β-D-glucopyranosyl)-4-fluoro-3-(5-(3-cyanophenyl)-2-thienylmethyl)benzene,    or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

The pharmaceutically acceptable salt of the compounds of the formula (I)includes, for example, a salt with an alkali metal such as lithium,sodium, potassium, etc.; a salt with an alkaline earth metal such ascalcium, magnesium, etc.; a salt with zinc or aluminum; a salt with anorganic base such as ammonium, choline, diethanolamine, lysine,ethylenediamine, t-butylamine, t-octylamine,tris(hydroxymethyl)aminomethane, N-methyl glucosamine, triethanolamineand dehydroabietylamine; a salt with an inorganic acid such ashydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,nitric acid, phosphoric acid, etc.; or a salt with an organic acid suchas formic acid, acetic acid, propionic acid, oxalic acid, malonic acid,succinic acid, fumaric acid, maleic acid, lactic acid, malic acid,tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, etc.; or a salt with an acidic amino acid such asaspartic acid, glutamic acid, etc.

The term “prodrug” means an ester or carbonate, which is formed byreacting one or more hydroxy groups of the compound of the formula (I)with an acylating agent substituted by an alkyl, an alkoxy or an aryl bya conventional method to produce acetate, pivalate, methylcarbonate,benzoate, etc. Further, the prodrug includes also an ester or amide,which is similarly formed by reacting one or more hydroxy groups of thecompound of the formula (I) with an α-amino acid or a β-amino acid, etc.using a condensing agent by a conventional method.

The compounds of formula (I) also includes a mixture of stereoisomers,or each pure or substantially pure isomer. For example, the presentcompound may optionally have one or more asymmetric centers at a carbonatom containing any one of substituents. Therefore, the compounds of theformula (I) may exist in the form of enantiomer or diastereomer, or amixture thereof. When the compounds of formula (I) contains a doublebond, the present compound may exist in the form of geometric isomerism(cis-compound, trans-compound), and when the compounds of formula (I)contains an unsaturated bond such as carbonyl, then the present compoundmay exist in the form of a tautomer, and the present compound alsoincludes these isomers or a mixture thereof. The starting compound inthe form of a racemic mixture, enantiomer or diastereomer may be used inthe processes for preparing the present compound. When the presentcompound is obtained in the form of a diastereomer or enantiomer, theycan be separated by a conventional method such as chromatography orfractional crystallization.

In addition, the compounds of formula (I) include an intramolecularsalt, hydrate, solvate or polymorphism thereof.

The methods of the present inventions are directed to the treatment andor prevention (including delay in the progression or onset of) of“glucose-related disorders”. As used herein, the term “glucose relateddisorder” shall be defined as any disorder which is characterized by oris developed as a consequence of elevated glucose levels.Glucose-related disorders shall include diabetes mellitus, diabeticretinopathy, diabetic neuropathy, diabetic nephropathy, delayed woundhealing, insulin resistance, hyperglycemia, hyperinsulinemia, elevatedblood levels of fatty acids, elevated blood levels of glucose,hyperlipidemia, obesity, hypertriglyceridemia, Syndrome X, diabeticcomplications, atherosclerosis, or hypertension. In particuler, the“glucose related-disorder” is diabetes mellitus (type 1 and type 2diabetes mellitus, etc.), diabetic complications (such as diabeticretinopathy, diabetic neuropathy, diabetic nephropathy), obesity, orpostprandial hyperglycemia.

In an embodiment of the present invention, the glucose related disorderis selected from the group consisting of diabetes mellitus, diabeticretinopathy, diabetic neuropathy, diabetic nephropathy, delayed woundhealing, insulin resistance, hyperglycemia, hyperinsulinemia, elevatedblood levels of fatty acids, hyperlipidemia, obesity,hypertriglyceridemia, Syndrome X, diabetic complications,atherosclerosis and hypertension.

In another embodiment of the present invention, the glucose relateddisorder is selected from the group consisting of type 1 diabetesmellitus, type 2 diabetes mellitus, diabetic retinopathy, diabeticneuropathy, diabetic nephropathy, obesity and postprandialhyperglycemia. In another embodiment of the present invention, theglucose related disorder is selected from the group consisting of type 1diabetes mellitus, type 2 diabetes mellitus, diabetic retinopathy,diabetic neuropathy, diabetic nephropathy, obesity, and delayed woundhealing. In another embodiment of the present invention, the glucoserelated disorders is selected from the group consisting of poor glycemiccontrol, Type 2 Diabetes Mellitus, Syndrome X, gestational diabetes,insulin resistance, hyperglycemia. In another embodiment of the presentinvention, the glucose related disorder is Type 2 diabetes mellitus.

In another embodiment, the glucose related disorder is selected from thegroup consisting of elevated glucose level, pre-diabetes, impaired oralglucose tolerance, poor glycemic control, Type 2 Diabetes Mellitus,Syndrome X (also known as metabolic syndrome), gestational diabetes,insulin resistance, and hyperglycemia.

Treatment of glucose related disorders may comprise lowering glucoselevels, improving glycemic control, decreasing insulin resistance and/orpreventing the development of a glucose related disorder (for examplepreventing a patient suffering from impaired oral glucose tolerance orelevated glucose levels from developing Type 2 diabetes mellitus).

As used herein, the terms “Syndrome X”, “Metabolic Syndrome” and“Metabolic Syndrome X” shall mean a disorder that presents risk factorsfor the development of Type 2 diabetes mellitus and cardiovasculardisease and is characterized by insulin resistance and hyperinsulinemiaand may be accompanied by one or more of the following: (a) glucoseintolerance, (b) Type 2 diabetes, (c) dyslipidemia, (d) hypertension and(e) obesity.

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

As used herein, unless otherwise noted, the terms “treating”,“treatment” and the like, shall include the management and care of asubject or patient (preferably mammal, more preferably human) for thepurpose of combating a disease, condition, or disorder and includes theadministration of a compound of the present invention to prevent theonset of the symptoms or complications, alleviate the symptoms orcomplications, or eliminate the disease, condition, or disorder.

As used herein, unless otherwise noted, the term “prevention” shallinclude (a) reduction in the frequency of one or more symptoms; (b)reduction in the severity of one or more symptoms; (c) the delay oravoidance of the development of additional symptoms; and/or (d) delay oravoidance of the development of the disorder or condition.

One skilled in the art will recognize that wherein the present inventionis directed to methods of prevention, a subject in need of thereof (i.e.a subject in need of prevention) shall include any subject or patient(preferably a mammal, more preferably a human) who has experienced orexhibited at least one symptom of the disorder, disease or condition tobe prevented. Further, a subject in need thereof may additionally be asubject (preferably a mammal, more preferably a human) who has notexhibited any symptoms of the disorder, disease or condition to beprevented, but who has been deemed by a physician, clinician or othermedical profession to be at risk of developing said disorder, disease orcondition. For example, the subject may be deemed at risk of developinga disorder, disease or condition (and therefore in need of prevention orpreventive treatment) as a consequence of the subject's medical history,including, but not limited to, family history, pre-disposition,co-existing (comorbid) disorders or conditions, genetic testing, and thelike.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated.

Wherein the present invention is directed to co-therapy or combinationtherapy, comprising administration of (a) metformin or apharmaceutically acceptable salt thereof and (b) a compound of formula(I) or a pharmaceutically acceptable salt thereof, “therapeuticallyeffective amount” shall mean that amount of the combination of agentstaken together so that the combined effect elicits the desiredbiological or medicinal response. For example, the therapeuticallyeffective amount of co-therapy comprising administration of (a)metformin or a pharmaceutically acceptable salt thereof and (b) acompound of formula (I) or a pharmaceutically acceptable salt thereof,would be the amount of (a) the metformin or a pharmaceuticallyacceptable salt thereof and (b) the compound of formula (I) orpharmaceutically acceptable salt thereof that when taken together orsequentially have a combined effect that is therapeutically effective.Further, it will be recognized by one skilled in the art that in thecase of co-therapy with a therapeutically effective amount, as in theexample above, the amount of the (a) metformin or pharmaceuticallyacceptable salt thereof and/or the amount of the (b) compound of formula(I) or pharmaceutically acceptable salt thereof individually may or maynot be therapeutically effective.

One skilled in the art will further recognize that the term“therapeutically effective amount” of co-therapy comprisingadministration of (a) glyburide, and (b) a compound of formula (I) or apharmaceutically acceptable salt thereof shall mean that amount of theglyburide and the amount of the compound of formula (I) orpharmaceutically acceptable salt thereof, that when taken together orsequentially have a combined effect that is therapeutically effective;and further that the amount of each of said components individually mayor may not be therapeutically effective.

One skilled in the art will further recognize that the “therapeuticallyeffective amount” of co-therapy comprising administration of (a)metformin or a pharmaceutically acceptable salt thereof, (b) a compoundof formula (I) or a pharmaceutically acceptable salt thereof and (c) asulfonylurea (preferably glyburide) or pharmaceutically acceptable saltthereof shall mean that amount of each of the components that that whentaken together or sequentially have a combined effect that istherapeutically effective; and further that the amount of each of thecomponents individually may or may not be therapeutically effective.

As used herein, the terms “co-therapy” and “combination therapy” shallmean treatment of a subject in need thereof by administering (a)metformin or a pharmaceutically acceptable salt thereof (b) a compoundof formula (I) or pharmaceutically acceptable salt thereof andoptionally (c) a sulfonylurea (preferably glyburide) or pharmaceuticallyacceptable salt thereof, wherein the (a) metformin or a pharmaceuticallyacceptable salt thereof, the (b) compound of formula (I) orpharmaceutically acceptable salt thereof and optionally (c) thesulfonylurea (preferably glyburide) or pharmaceutically acceptable saltthereof are administered by any suitable means, simultaneously,sequentially, separately or in a single pharmaceutical dosage form.Where the (a) metformin or a pharmaceutically acceptable salt thereof,the (b) compound of formula (I) or pharmaceutically acceptable saltthereof and optionally (c) the sulfonylurea (preferably glyburide) orpharmaceutically acceptable salt thereof are administered in separatedosage forms, the number of dosages administered per day for eachcompound may be the same or different. The (a) metformin or apharmaceutically acceptable salt thereof, the (b) compound of formula(I) or pharmaceutically acceptable salt thereof and optionally (c) thesulfonylurea (preferably glyburide) or pharmaceutically acceptable saltthereof, may be administered via the same or different routes ofadministration. Examples of suitable methods of administration include,but are not limited to, oral, intravenous (iv), intramuscular (im),subcutaneous (sc), transdermal, and rectal. Compounds may also beadministered directly to the nervous system including, but not limitedto, intracerebral, intraventricular, intracerebroventricular,intrathecal, intracisternal, intraspinal and/or peri-spinal routes ofadministration by delivery via intracranial or intravertebral needlesand/or catheters with or without pump devices. The (a) metformin or apharmaceutically acceptable salt thereof, the (b) compound of formula(I) or pharmaceutically acceptable salt thereof and optionally (c) thesulfonylurea (preferably glyburide) or pharmaceutically acceptable saltthere may be administered according to simultaneous or alternatingregimens, at the same or different times during the course of thetherapy, concurrently in divided or single forms. One skilled in the artwill further recognize that the above discussion related to “co-therapy”and “combination therapy” will similarly apply to co-therapy orcombination therapy for the treatment of a glucose related disordercomprising administration to a subject in need thereof of (a) glyburide,and (b) a compound of formula (I) or pharmaceutically acceptable saltthereof.

To provide a more concise description, some of the quantitativeexpressions herein are recited as a range from about amount X to aboutamount Y. It is understood that wherein a range is recited, the range isnot limited to the recited upper and lower bounds, but rather includesthe full range from about amount X through about amount Y, or any amountor range therein.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including approximations due to the experimental and/or measurementconditions for such given value.

The present invention further comprises pharmaceutical compositionscontaining (a) metformin or a pharmaceutically acceptable salt thereofand (b) a compound of formula (I) or pharmaceutically acceptable saltthereof with a pharmaceutically acceptable excipient. Pharmaceuticalcompositions of the present invention described herein as the activeingredient can be prepared by intimately mixing the (a) metformin or apharmaceutically acceptable salt thereof and the (b) compound of formula(I) or pharmaceutically acceptable salt thereof with a pharmaceuticalexcipient according to conventional pharmaceutical compoundingtechniques.

The present invention further comprises pharmaceutical compositionscontaining (a) glyburide, and (b) a compound of formula (I) orpharmaceutically acceptable salt thereof with a pharmaceuticallyacceptable excipient. Pharmaceutical compositions of the presentinvention described herein as the active ingredient can be prepared byintimately mixing the (a) glyburide, and the (b) compound of formula (I)or pharmaceutically acceptable salt thereof with a pharmaceuticalexcipient according to conventional pharmaceutical compoundingtechniques.

The present invention further comprises pharmaceutical compositionscontaining (a) metformin or a pharmaceutically acceptable salt thereof,(b) a compound of formula (I) or pharmaceutically acceptable saltthereof, (c) a sulfonylurea or pharmaceutically acceptable salt thereofwith a pharmaceutically acceptable excipient. Pharmaceuticalcompositions of the present invention described herein as the activeingredient can be prepared by intimately mixing the (a) metformin or apharmaceutically acceptable salt thereof, the (b) compound of formula(I) or pharmaceutically acceptable salt thereof and the (c) sulfonylureaor pharmaceutically acceptable salt thereof with a pharmaceuticalexcipient according to conventional pharmaceutical compoundingtechniques.

The pharmaceutically acceptable excipient may take a wide variety offorms depending upon the desired route of administration (e.g., oral,parenteral). Thus for liquid oral preparations such as suspensions,elixirs and solutions, suitable excipients and additives include water,glycols, oils, alcohols, flavoring agents, preservatives, stabilizers,coloring agents and the like; for solid oral preparations, such aspowders, capsules and tablets, suitable excipients and additives includediluents, granulating agents, lubricants, binders, disintegratingagents, drug release controlling hydrophilic polymer, drug releasecontrolling hydrophobic polymers, wetting agents and the like. Solidoral preparations may also be coated with substances such as sugars,cellulosic ethers, and acrylic polymers for extended release or may beenteric-coated so as to modulate major site of absorption. Forparenteral administration, the excipient will usually consist of sterilewater and other ingredients may be added to increase solubility orpreservation. Injectable suspensions or solutions may also be preparedutilizing aqueous excipients along with appropriate additives.

To prepare the pharmaceutical compositions of this invention, thecompound of formula (I) or pharmaceutically acceptable salt thereof andthe (a) metformin or a pharmaceutically acceptable salt thereof and/orthe (b) sulfonylurea (preferably glyburide) or pharmaceuticallyacceptable salt thereof, as the active ingredients, are intimatelyadmixed with a pharmaceutical excipient according to conventionalpharmaceutical compounding techniques, which excipient may take a widevariety of forms depending of the form of preparation desired foradministration, e.g., oral or parenteral such as intramuscular. Inpreparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed. Thus, for liquid oralpreparations, such as for example, suspensions, elixirs and solutions,suitable excipients and additives include water, glycols, oils,alcohols, flavoring agents, preservatives, coloring agents and the like;for solid oral preparations such as, for example, powders, capsules, andtablets (including caplets), suitable excipients and additives includediluents, granulating agents, lubricants, binders, disintegratingagents, drug release controlling hydrophilic polymers, drug releasecontrolling or hydrophobic polymers, wetting agents, and the like.Because of their ease in administration, tablets and capsules representthe most advantageous oral dosage unit form, in which case solidpharmaceutical excipients are obviously employed. If desired, tabletsmay be sugar coated or may be enteric coated by standard techniques. Forparenterals, the excipient will usually comprise sterile water, throughother ingredients, for example, for purposes such as aiding solubilityor for preservation, may be included. Injectable suspensions may also beprepared, in which case appropriate liquid excipients, suspending agentsand the like may be employed. The pharmaceutical compositions describedherein will contain, per dosage unit, e.g., tablet, capsule, powder,injection, teaspoonful and the like, an amount of the activeingredient(s) necessary to deliver an effective dose as described above.The pharmaceutical compositions herein will contain, per unit dosageunit, e.g., tablet, capsule, powder, injection, suppository, teaspoonfuland the like, of from about 0.01 to about 2,000 mg, or any amount orrange therein, independently, of each of the (a) metformin or apharmaceutically acceptable salt thereof, the (b) compound of formula(I) or pharmaceutically acceptable salt thereof, and/or the (c)sulfonylurea (preferably glyburide) or pharmaceutically acceptable saltthereof. The pharmaceutical compositions described herein may be givenat a suitably selected therapeutically effective dosage, which may bevaried depending upon the requirement of the patients, the severity ofthe condition being treated and the compound being employed. The use ofeither daily administration or post-periodic dosing may be employed.

Preferably these pharmaceutical compositions are in unit dosage formsfrom such as tablets, pills, capsules, powders, granules, sterileparenteral solutions or suspensions, metered aerosol or liquid sprays,drops, ampoules, autoinjector devices or suppositories; for oralparenteral, intranasal, sublingual or rectal administration, or foradministration by inhalation or insufflation. Alternatively, thepharmaceutical composition may be presented in a form suitable foronce-weekly or once-monthly administration; for example, an insolublesalt of the active compound(s), such as the decanoate salt, may beadapted to provide a depot preparation for intramuscular injection.

For preparing solid compositions such as tablets, the principal activeingredient(s) are mixed with a pharmaceutical excipient, e.g.conventional tableting ingredients such as corn starch, lactose,sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalciumphosphate or gums, and other pharmaceutical diluents, e.g. water, toform a solid formulation composition containing a mixture of the activeingredient(s). The tablets or pills of the pharmaceutical composition ofthe present invention can be coated or otherwise compounded to provide adosage form affording the advantage of prolonged action. For example,the tablet or pill can comprise an inner dosage and an outer dosagecomponent, the latter being in the form of an envelope over the former.The two components can be separated by an enteric layer which serves toresist disintegration in the stomach and permits the inner component topass intact into the duodenum or to be delayed in release. A variety ofmaterial can be used for such enteric layers or coatings, such materialsincluding a number of polymeric acids with such materials as shellac,cetyl alcohol and cellulose acetate.

The liquid forms in which the pharmaceutical compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions, include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

Advantageously, the pharmaceutical compositions of the present inventionmay be administered in a single daily dose, or the total daily dosagemay be administered in divided doses of two, three or four times daily.Furthermore, the pharmaceutical compositions of the present inventioncan be administered in intranasal form via topical use of suitableintranasal vehicles, or via transdermal skin patches well known to thoseof ordinary skill in that art. To be administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.

In certain embodiments, for oral administration in the form of a tabletor capsule, the active drug component(s) can be combined with an oral,non-toxic pharmaceutically acceptable inert excipient such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders; lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium oleate, sodium stearate, magnesiumstearate, sodium benzoate, sodium acetate, sodium chloride, and thelike. Disintegrators include, without limitation, starch, sodium starchglycolate, croscamellose sodium, crospovidone, methyl cellulose, agar,bentonite, xanthan gum, and the like. The liquid forms in suitablyflavored suspending or dispersing agents such as the synthetic andnatural gums, for example, tragacanth, acacia, methyl-cellulose and thelike. For parenteral administration, sterile suspensions and solutionsare desired. Isotonic preparations which generally contain suitablepreservatives are employed when intravenous administration is desired.

The pharmaceutical compositions of the present invention may be preparedaccording to known methods and employing known processes and equipment,as disclosed, for example in Pharmaceutical Sciences, Remington, 17thEd., pp. 1585-1594 (1985); Chemical Engineers Handbook, Perry, 6th Ed.,pp. 21-13 to 21-19 (1984); Journal of Pharmaceutical Sciences, Parrot,Vol. 61, No. 6, pp. 813-829 (1974); and Chemical Engineer, Hixon, pp.94-103 (1990).

Granules for the pharmaceutical compositions of the present inventionmay, for example, be prepared by comminution, which produces the desiredsize of the active ingredient and the desired size of any accompanyingpharmaceutically acceptable excipient(s). Suitable means for producingthe desired particles include, but are not limited to, granulation,spray drying, sieving, lyophilization, crushing, grinding, jet milling,micronizing and chopping to produce the intended particle size. Theprocess can be performed by size reduction equipment, such as amicropulverizer mill, a fluid energy-grinding mill, a grinding mill, aroller mill, a hammer mill, an attrition mill, a chaser mill, a ballmill, a vibrating ball mill, an impact pulverizer mill, a centrifugalpulverizer, a coarse crusher and a fine crusher. The size of theparticle can be ascertained by screening, including a grizzly screen, aflat screen, a vibrating screen, a revolving screen, a shaking screen,an oscillating screen and a reciprocating screen. The granules are then,for example, pressed according to known methods to yield a tablet.

Granules for the pharmaceutical compositions of the present inventionmay alternatively be manufactured according to the wet granulationtechnique. In the wet granulation technique, solid particles are wettedand bound together by a binder solution consisting essentially of agranulation solvent, a binder, and optionally other excipients. Theactive ingredient (for example, the compound of formula (I-X) orpharmaceutically acceptable salt thereof) may be granulated as solidparticles together with or absent other solid excipients, or ispartially dissolved in the binder solution. The solid particles can bemixed by means of mechanical agitation (using for example, a low or highshear mixer) or may be fluidized by a gas (as in fluid bed granulation).The granulating fluid is added until a wet blend is produced, which wetmass blend is then forced through a predetermined screen and dried in afluid bed dryer. The blend is dried for about 18 to about 24 hours at atemperature in the range of from about 24° C. to about 35° C. in aforced-air oven. The dried granules are then sized, according to knownmethods. The dried granules are then sized. Next, magnesium stearate, oranother suitable lubricant (if desired) and other excipient materials(as appropriate) are added to the granulation, and the granulation isput into milling jar sand mixed on a jar mill for 10 minutes. For thepreparation of tablets, the resulting composition is pressed into alayer, for example, in a Manesty® press or a Korsch LCT press. In anexample, the speed of the press is set at 15 rpm and the maximum loadset at about 4 tons.

Alternatively, the active ingredient and excipient(s) may be blended aspowdered ingredients in a fluid bed granulator. After the powderedingredients are dry blended in the granulator, a granulating fluid, forexample, polyvinylpyrrolidone in water, is sprayed onto the powders. Theresulting agglomerated materials are then dried in the granulator. Thisprocess granulates all the ingredients present therein while adding thegranulating fluid. After the granules are dried, a lubricant, such asstearic acid or magnesium stearate, is mixed into the granulation usinga blender e.g., V-blender or tote blender. The granules are then pressedand coated in the manner described above.

Exemplary solvents suitable for manufacturing the pharmaceuticalcomposition components comprise aqueous or inert organic solvents thatdo not adversely harm the materials used in the system. The solventsbroadly include members selected from the group consisting of aqueoussolvents, alcohols, ketones, esters, ethers, aliphatic hydrocarbons,halogenated solvents, cycloaliphatics, aromatics, heterocyclic solventsand mixtures thereof. Typical solvents include acetone, diacetonealcohol, methanol, ethanol, isopropyl alcohol, butyl alcohol, methylacetate, ethylacetate, isopropyl acetate, n-butyl acetate, methylisobutyl ketone, methyl propyl ketone, nhexane, n-heptane, ethyleneglycol monoethyl ether, ethylene glycol monoethyl acetate, methylenedichloride, ethylene dichloride, propylene dichloride, carbontetrachloridenitroethane, nitropropane tetrachloroethane, ethyl ether,isopropyl ether, cyclohexane, cyclooctane, benzene, toluene, naphtha,1,4-dioxane, tetrahydrofuran, diglyme, water, aqueous solventscontaining inorganic salts such as sodium chloride, calcium chloride,and the like, and mixtures thereof such as acetone and water, acetoneand methanol, acetone and ethyl alcohol, methylene dichloride andmethanol, and ethylene dichloride and methanol.

Where desired, pan coating may be used to provide a completed dosageform. In the pan coating system, the coating composition is deposited bysuccessive spraying onto the compressed tablet, accompanied by tumblingin a rotating pan. A pan coater is commonly used because of itsavailability at commercial scale. Other techniques can be used forcoating the tablet. Once coated, the tablet is dried in, for example,the same equipment of in a forced-air oven or in a temperature andhumidity controlled oven to free the dosage form of solvent(s) used inthe manufacturing. Drying conditions are conventionally chosen on thebasis of available equipment, ambient conditions, solvents, coatings,coating thickness, and the like.

Other coating techniques can also be employed. For example, onealternative technique uses an air-suspension procedure. This procedureconsists of suspending and tumbling the tablet in a current of air,until a coating is applied. The air-suspension procedure is describedin, for example, U.S. Pat. No. 2,799,241; in J. Am. Pharm. Assoc., Vol.48, pp. 451-459 (1959); and, ibid., Vol. 49, pp. 82-84 (1960). Thetablet also can be coated with a Wurster® air-suspension coater using,for example, methylene dichloride methanol as a co-solvent for thecoating material. An Aeromatic® air-suspension coater can be usedemploying a co-solvent.

The co-therapy comprising (a) metformin or a pharmaceutically acceptablesalt thereof and (b) a compound of formula (I) or pharmaceuticallyacceptable salt thereof, of the present invention may be administered inany of the foregoing compositions and according to dosage regimensestablished in the art whenever treatment of a glucose related disorderis required.

The co-therapy comprising (a) glyburide, and (b) a compound of formula(I) or pharmaceutically acceptable salt thereof, of the presentinvention may be administered in any of the foregoing compositions andaccording to dosage regimens established in the art whenever treatmentof a glucose related disorder is required.

The co-therapy comprising (a) metformin or a pharmaceutically acceptablesalt thereof, (b) a compound of formula (I) or pharmaceuticallyacceptable salt thereof, and (c) a sulfonylurea (preferably glyburide)or pharmaceutically acceptable salt thereof, of the present inventionmay be administered in any of the foregoing compositions and accordingto dosage regimens established in the art whenever treatment of aglucose related disorder is required.

In an embodiment, for oral administration, the compositions arepreferably provided in the form of tablets containing, 50, 100, 150,200, 250, 500, 750, 850, 1000, 1500 or 2000 milligrams of the metforminor pharmaceutically acceptable salt thereof (preferably metforminhydrochloride); and further containing 1, 5, 10, 25, 50, 100, 150, 200,250, 300 or 500 milligrams of the compound of formula (I) orpharmaceutically acceptable salt thereof. In another embodiment, fororal administration, the compositions are preferably provided in theform of tablets containing, 1.0, 2.5, 5.0, 7.5, 10.0, 12.5, 15 or 20milligrams, of the glyburide; and further containing 1, 5, 10, 25, 50,100, 150, 200, 250, 300 or 500 milligrams of the compound of formula (I)or pharmaceutically acceptable salt thereof. In another embodiment, fororal administration, the compositions are preferably provided in theform of tablets containing, 50, 100, 150, 200, 250, 500, 750, 850, 1000,1500 or 2000 milligrams of the metformin or pharmaceutically acceptablesalt thereof (preferably metformin hydrochloride); further containing 1,5, 10, 25, 50, 100, 150, 200, 250, 300 or 500 milligrams of the compoundof formula (I) or pharmaceutically acceptable salt thereof (preferably acompound of formula (I-X) or pharmaceutically acceptable salt thereof ora compound of formula (I-Y) or pharmaceutically acceptable saltthereof), and further containing 1.0, 2.5, 5.0, 7.5, 10.0, 12.5, 15, 20,25, 50, 100, 250, 500 or 1000 milligrams, of the sulfonylurea orpharmaceutically acceptable salt thereof.

Preferably, the metformin or pharmaceutically acceptable salt thereof(more preferably, metformin hydrochloride) is administered at a dosagelevel of from about 0.01 mg/kg to about 200 mg/kg of body weight perday, or from about 0.5 mg/kg to about 50 mg/kg of body weight per day,or any amount or range therein. Preferably, the range is from about 1.0to about 50.0 mg/kg of body weight per day, or any amount or rangetherein, more preferably, from about 5 mg/kg to about 30 mg/kg, or anyamount or range therein, more preferably, from about 5 to about 20 mg/kgof body weight per day, or any amount or range therein. In anembodiment, an effective amount of the metformin or pharmaceuticallyacceptable salt thereof is supplied at a dosage level of 250 mg, 500 mg,750 mg, 1000 mg or 2000 mg, or any amount or range therein.

Preferably, the glyburide is administered at a dosage level of fromabout 0.01 mg/kg to about 0.5 mg/kg of body weight per day, or fromabout 0.01 mg/kg to about 0.3 mg/kg of body weight per day, or anyamount or range therein. In an embodiment, an effective amount of theglyburide is supplied at a dosage level of 1.0 mg, 2.5 mg, 5.0 mg, 7.5mg, 10.0 mg, 12.5 mg, 15 mg, or 20 mg, or any amount or range therein.

Preferably, the compound of formula (I) or pharmaceutically acceptablesalt thereof is administered at a dosage level of from about 0.01 mg/kgto about 500 mg/kg of body weight per day, or 0.01 mg/kg to about 200mg/kg of body weight per day, or any amount or range therein.Preferably, the range is from about 0.01 to about 50 mg/kg of bodyweight per day, or any amount or range therein, more preferably, fromabout 0.05 mg/kg to about 10 mg/kg, or any amount or range therein, morepreferably, from about 1 to about 5 mg/kg of body weight per day, or anyamount or range therein. In an embodiment, an effective amount of thecompound of formula (I) or pharmaceutically acceptable salt thereof issupplied at a dosage level of 10 mg, 25 mg, 50 mg, 100 mg, 150 mg or 300mg, or any amount or range therein. Preferably, the sulfonylurea orpharmaceutically acceptable salt thereof is administered at a dosagelevel of from about 0.01 mg/kg to about 200 mg/kg of body weight perday, or any amount or range therein. Preferably, the range is from about0.01 to about 50 mg/kg of body weight per day. In an embodiment, aneffective amount of the sulfonylurea or pharmaceutically acceptable saltthereof is supplied at a dosage level of 1.0 mg, 2.5 mg, 5.0 mg, 10 mg,25 mg, 50 mg, 100 mg, 150 mg, 250 mg, 500 mg, 100 mg, or any amount orrange therein. The co-therapy of the present invention may beadministered on a regimen of 1 to 4 times per day.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with for example, the mode ofadministration, the strength of the preparation, the mode ofadministration, and the advancement of the disease condition. Inaddition, factors associated with the particular patient being treated,including patient age, weight, diet and time of administration, willresult in the need to adjust dosages.

One skilled in the art will recognize that, both in vivo and in vitrotrials using suitable, known and generally accepted cell and/or animalmodels are predictive of the ability of a test compound or co-therapy totreat or prevent a given disorder. One skilled in the art will furtherrecognize that human clinical trials including first-in-human, doseranging and efficacy trials, in healthy patients and/or those sufferingfrom a given disorder, may be completed according to methods well knownin the clinical and medical arts.

The following Examples are set forth to aid in the understanding of theinvention, and are not intended and should not be construed to limit inany way the invention set forth in the claims which follow thereafter.

An ability and unexpected synergistic effect of co-therapy of metforminand the compound of formula (I) to treat glucose related disorders, forexample, Type 2 diabetes mellitus and Syndrome X, is based on thefollowing animal study.

Example 1 In Vivo Mouse Study

Male C57BL/6 mice (total of 100 mice) were fed with a high fat diet fromthe age of 3 weeks to 6 weeks (total 3 weeks). After 3 weeks on a highfat diet, all the mice received a single-dose ip injection ofSteptozotocin (STZ) (100 mg/kg, in 0.05 mol/L citric acid, pH4.5, 10mg/ml). All the mice were then kept on a high fat diet for another 3weeks. Those mice with fasted blood glucose levels >7 mM and <15 mM wereselected for the study.

At the start of the pre-dose period, each mouse was assigned a predosenumber, which was indicated on its cage card. After assignment to dosagegroups, each mouse was assigned a unique study identification number(which will be indicated on its cage card) and identified by permanentmarker on its tail. Mice were housed 5 mice per cage in stainless steelcages. The study room was maintained on a 12-hour light/dark cycle(light/dark cycle may be interrupted for study-related activities),within a temperature range of 64° F. to 79° F., and a relative humidityrange of 30% to 70%. The temperature and humidity ranges will bemonitored by a hygrothermograph. Mice were fed ad libitum (except wherenoted) with high-fat diet prepared in Southern University. Water wasprovided ad libitum by water bottles.

Study Design:

The quarantine period was 5 days. The test compound or vehicle wasadministered orally by gavage. The dosage levels were chosen torepresent a range of exposures with pharmacology effects.

Mice were selected on the basis of pre-dose evaluations at day −1 andrandomly assigned to groups using a computer-generated randomizationmethod based on body weight and fasted blood glucose levels. The meanvalues of body weight and fasted blood glucose level of each group weresimilar (within <5% variation).

The mice were randomly divided into six testing group of 10 mice pergroup. Each group was treated for 3 weeks, via oral administration, withone of the following regimens: (a) vehicle; (b) the compound of formula(I-Y) at 1 mg/kg; (c) the compound of formula (I-Y) at 10 mg/kg; (d)metformin at 500 mg/kg; (e) a combination of the compound of formula(I-Y) at 1 mg/kg and metformin at 500 mg/kg; and (f) a combination ofthe compound of formula (I-Y) at 10 mg/kg and metformin at 500 mg/kg.

On Day 1 (the first day of dosing), dosing at all dose levels wasinitiated. All groups were then dosed for 20 additional days. Thefollowing pharmacological parameters were measured during and at the endof this study: (a) fed blood glucose were measured at day 1, 7, 14, and21 day before dosing; (b) body weight of each mouse was measured at day−1 (for grouping), 1, 7, 14, and 21, after blood glucose measurement;and (c) 24 hr food intake (average of 5 mice per cage) was measured atday 1, 7, 14, and 20.

On day 18 of treatment, mice were fasted overnight (5 pm-8 am), after achange to a new cage. The following morning, a basal fasted bloodglucose level was determined. Then, glucose solution (20% glucose, 2g/kg body weight, 1 ml/100 g of body weight, prepared freshly beforeoral glucose tolerance test, (OGTT) was administrated via oral gavage.Blood glucose levels were measured using tail blood at 30, 60, and 120min after glucose challenge. Food was replaced after the last time pointof blood glucose measurement.

The pharmacological significance of any findings was determined based onstatistical analysis and historical control data. Statistical analyseswere performed utilizing GraphPadPRISM.

The compound of formula (I-Y) alone and in combination with metforminwas tested according to the procedure as described above, with resultsas listed in Table 1, below.

TABLE 1 in vivo Mouse Assay Results Blood Glucose AUC Fed Glucose FastedGlucose during OGTT Treatment (mg/dL) (mg/dL) (mg/dL * 2 h) Vehicle421.5 ± 25.9 87.0 ± 6.1 36951 ± 2592 Cmpd (I-Y) (1 mg/kg) 360.7 ± 15.777.8 ± 4.9 31562 ± 1447 Cmpd (I-Y) (10 mg/kg) 290.5 ± 24.8 66.9 ± 3.125209 ± 894  Metformin (500 mg/kg) 345.4 ± 28.4 74.7 ± 3.8 34023 ± 1618Cmpd (I-Y) (1 mg/kg) + 290.0 ± 15.4  75.7 ± 11.3 28934 ± 1464 Metformin(500 mg/kg) Cmpd (I-Y) (10 mg/kg) + 223.7 ± 12.2 54.1 ± 4.1 19395 ± 584 Metformin (500 mg/kg) Blood Glucose AUC Fed Glucose Fasted Glucoseduring OGTT (% relative to (% relative to (% relative to the Treatmentthe Vehicle) the Vehicle) Vehicle) Vehicle 100% ± 6%  100.0% ± 7.0% 100% ± 7%  Cmpd (I-Y) (1 mg/kg) 86% ± 4% 89.4% ± 5.7% 85% ± 4% Cmpd(I-Y) (10 mg/kg) 69% ± 6% 76.9% ± 3.6% 68% ± 2% Metformin (500 mg/kg)82% ± 7% 85.9% ± 4.4% 92% ± 4% Cmpd (I-Y) (1 mg/kg) + 69% ± 4%  87.0% ±13.0% 78% ± 4% Metformin (500 mg/kg) Cmpd (I-Y) (10 mg/kg) + 53% ± 3%62.2% ± 4.7% 52% ± 2% Metformin (500 mg/kg)

Example 2 In Vivo Mouse Study

Male ob/ob mice (8-week old, ˜50 g) were housed 2 mice per cage in atemperature-controlled room with 12-hour light/dark cycle. The mice wereallowed ad libitum access to water and chow (commercially supplieddiet). Mice were grouped into 6 test groups based on their body weightand fed blood glucose levels, as noted in Table 2, below.

TABLE 2 Mouse Treatment groups Group Treatment 1 Vehicle (0.5% Methocel)1 ml/100 g, P.O. 2 Compound of formula (I-X) @ 1.0 mpk: 1 ml/100 g, P.O.3 Compound of formula (I-X) @ 10.0 mpk: 1 ml/100 g, P.O. 4 MetforminHCl: 250 mpk: 1 ml/100 g, P.O. 5 Compound of formula (I-X) @ 1 mpkMetformin HCl: 250 mpk, 1 ml/100 g, P.O. 6 Compound of formula (I-X) @10 mpk Metformin HCl: 250 mpk, 1 ml/100 g, P.O.

Study Design:

On the first morning, the mice were grouped as noted above and fedglucose. The mice were then dosed with vehicle or test compound(s) viagavage at 4:00 pm each day for 22 days q.d. The compound of formula(I-X) was dosed at 1 mg/kg or 10 mg/kg (as noted in the result tablebelow) with or without treatment with metformin HCl at a dosage of 250mg/kg.

Body weight, food intake and fed blood glucose levels were measuredweekly. An oral glucose tolerance test (OGTT) was conducted on the miceon day 18, after overnight fasting. Glucose concentrations of 0.5 g/kgBW, and blood glucose levels of OGTT were measured using a Glucometer att₀ (before glucose dosing), t₃₀, t₆₀, and t₁₂₀ corresponding to 30, 60and 120 minutes following administration. The administered glucosesolution was prepared at 0.5 g/kg using 12.5% glucose, 1 ml/250 g BW.

Following completion of the study, final body weight and blood glucoselevel of were collected and the mice in each group was sacrificed tocollect blood for biochemistry analysis, including fed blood glucoselevels, fasted blood glucose levels, blood glucose levels during OGTT,plasma insulin and body weight change.

The compound of formula (I-X) alone and in combination with metforminwas tested according to the procedure as described above, with resultsas listed in Table 3, below.

TABLE 3 in vivo ob/ob Mouse Assay Results Blood Glucose Fasted AUC FedGlucose Glucose during OGTT Treatment (mg/dL) (mg/dL) (mg/dL * 2 h)Vehicle 345 ± 19 174 ± 11 100 ± 5  Cmpd (I-X) (1 mg/kg) 312 ± 34 159 ±12 80 ± 4 Cmpd (I-X) (10 mg/kg) 254 ± 22  86 ± 4  48 ± 3 Metformin HCl(250 mg/kg) 371 ± 35 166 ± 16 91 ± 9 Cmpd (I-X) (1 mg/kg) + 285 ± 23 153± 12 77 ± 7 Metformin HCl (250 mg/kg) Cmpd (I-X) (10 mg/kg) + 216 ± 10110 ± 11 56 ± 3 Metformin HCl (250 mg/kg) Plasma Insulin Body WeightTreatment (ng/dL) (g) Vehicle 38.6 ± 3.3 54 ± 0.8 Cmpd (I-X) (1 mg/kg)46.3 ± 3.5 53 ± 0.8 Cmpd (I-X) (10 mg/kg) 44.0 ± 3.6 54 ± 0.8 MetforminHCl (250 mg/kg) 48.4 ± 2.0 52 ± 0.9 Cmpd (I-X) (1 mg/kg) + 52.6 ± 1.2 53± 0.8 Metformin HCl (250 mg/kg) Cmpd (I-X) (10 mg/kg) + 53.1 ± 1.4 51 ±1.0 Metformin HCl (250 mg/kg)

The results in Table 3 above indicate that the compound of formula (I-X)at 10 mg/kg significantly reduced blood glucose levels and improvedglucose excursion during OGTT. The results further showed no additive orsynergistic effect in mice treated with the combination of metformin andthe compound of formula (I-X). Additionally, the results show thatmetformin at 250 mg/kg did not have an effect on blood glucose control,suggesting that the ob/ob mouse is not a suitable animal model todemonstrate the activity of metformin (given the mechanism by whichmetformin acts on glucose levels). The lack of an additive and/orsynergistic effect for the combination of the compound of formula (I-X)and metformin, is therefore believed to be a result of this model'slimitation in demonstrating known anti-diabetic activity.

Example 3 Pharmaceutical Composition Combination of MetforminHydrochloride and the Compound of Formula (I-X)

A pharmaceutical composition comprising metformin hydrochloride and thecompound of formula (I-X) was prepared as follows, with Table 4, belowlisting the components in the formulation. Metformin HCl was purchasedas commercially available Drug Substance (DS) from Solmag S. P. AMulazzano (Via Della Vittoria 89, 26837 Cassino d'Alberi, Mulazzano,Italy).

TABLE 4 Combination Tablet Formulation mg/ Quanity/ Description Functiontablet % w/w Batch (g) Intragranular Additions Compound of Formula Drug200.0 14.69 132.2 (I-X) Substance-1 Metformin HCl Drug 1000.0 73.46660.8 Substance-2 Microcrystalline Cellulose Filler 59.2 4.35 39.1Povidone (K29/32)¹ Binder 54.50 4.00 36.0 Croscarmellose sodiumDisintegrant 40.80 3.00 27.3 Water² NA N/A Extragranular AdditionsMagnesium Stearate, 2257 Lubricant 6.8 0.50 4.5 Totals 100.0 1361.3100.0 899.6 ¹Added as 6% solids in solution ²Not in final formulation

Metformin hydrochloride, the compound of formula (I-X), microcrystallinecellulose (MCC) and croscarmellose sodium were screened and blended inbohle bin blender (L. B Bohle Maschinen+Verfhren GmbH, Ennigerloh,Germany). The resulting materials were fluidized in a Glatt Fluid bedprocessor (Glatt Air Techniques, Ramsay, N.J.) with 1.0 mm nozzle andaircap setting of 2. The binder (Povidone K29/32), as a 6% w/w solidssolution in water, was then sprayed onto the resulting granules. Themoisture level and granulation growth were monitored during the process,with samples taken every 10 minutes of the process. Moisture balance wasused to determine loss on drying (LOD).

The dried granulation was then lubricated with screened magnesiumstearate in a bohle bin blender. The final blend was compressed intotablets on a rotary press, Fette 1200i (Fette GmbH, Schwarzenbek,Germany) equipped with 0.830″×0.4095″ D-tooling and low quantity feeder.The Batch was compressed using two stations to the target tablet weight.Five different compression profiles were used to produce tablets.

For the five compression profile sub-batches, tablet weight variationwas less than 1% and friability was less than 0.5%. Tablet hardnessincreased with compression from 16 kp at 14.6 KN compression to 25 kp at31.3 KN compression, and corresponding tablet thickness decreased from7.32±0.3 mm at 14.6 KN to 6.84±0.3 mm at 31.3 KN. Disintegration timeincreased with compression from about 4:50 min at 14.6 KN compression toabout 9:40 min at 31.3 KN. A measure of the dissolution rate showed thatat 30 minutes, between about 85% to about 93% of the compound of formula(I-X) was released, and between about 94% and about 99% of the metforminhydrochloride was released.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

1. A method for treating a glucose related disorder comprisingadministering to a subject in need thereof a therapeutically effectiveamount of co-therapy comprising (a) metformin or a pharmaceuticallyacceptable salt thereof; and (b) a compound of formula (I)

wherein Ring A and Ring B are one of the followings: (1) Ring A is anoptionally substituted unsaturated monocyclic heterocyclic ring, andRing B is an optionally substituted unsaturated monocyclic heterocyclicring, an optionally substituted unsaturated fused heterobicyclic ring,or an optionally substituted benzene ring; or (2) Ring A is anoptionally substituted benzene ring, and Ring B is an optionallysubstituted unsaturated monocyclic heterocyclic ring, or an optionallysubstituted unsaturated fused heterobicyclic ring wherein Y is linked tothe heterocyclic ring of the fused heterobicyclic ring; or (3) Ring A isan optionally substituted unsaturated fused heterobicyclic ring, whereinthe sugar moiety X-(sugar) and the moiety —Y-(Ring B) are both on thesame heterocyclic ring of the fused heterobicyclic ring, and Ring B isan optionally substituted unsaturated monocyclic heterocyclic ring, anoptionally substituted unsaturated fused heterobicyclic ring, or anoptionally substituted benzene ring; X is a carbon atom or a nitrogenatom; and Y is —(CH₂)_(n)— (wherein n is 1 or 2); or a pharmaceuticallyacceptable salt thereof.
 2. A method as in claim 1, wherein the glucoserelated disorder is selected from the group consisting of diabetesmellitus, diabetic retinopathy, diabetic neuropathy, diabeticnephropathy, delayed wound healing, insulin resistance, hyperglycemia,hyperinsulinemia, elevated blood levels of fatty acids, elevated bloodlevels of glucose, hyperlipidemia, obesity, hypertriglyceridemia,Syndrome X, diabetic complications, atherosclerosis and hypertension. 3.A method as in claim 1, wherein the glucose related disorder is type 2diabetes mellitus.
 4. A method as in claim 1, wherein the compound offormula (I) is a compound of formula (I-X)

or pharmaceutically acceptable salt thereof.
 5. A method as in claim 4,wherein the compound of formula (I-X) is a crystalline hemihydrate.
 6. Amethod as in claim 1, wherein the metformin or pharmaceuticallyacceptable salt thereof is metformin hydrochloride; and wherein themetformin hydrochloride is administered at a dosage of between about 100mg and about 2000 mg.
 7. A method as in claim 1, wherein the compound offormula (I) or pharmaceutically acceptable salt thereof is administeredat a dosage in the range of from about 50 mg to about 500 mg.
 8. Amethod for treating a glucose related disorder comprising administeringto a subject in need thereof a therapeutically effective amount ofco-therapy comprising (a) metformin hydrochloride; and (b) a compound offormula (I-X)

or pharmaceutically acceptable salt thereof.
 9. A method as in claim 8,wherein the glucose related disorder is selected from the groupconsisting of diabetes mellitus, diabetic retinopathy, diabeticneuropathy, diabetic nephropathy, delayed wound healing, insulinresistance, hyperglycemia, hyperinsulinemia, elevated blood levels offatty acids, elevated blood levels of glucose, hyperlipidemia, obesity,hypertriglyceridemia, Syndrome X, diabetic complications,atherosclerosis and hypertension.
 10. A method as in claim 9, whereinthe glucose related disorder is type 2 diabetes mellitus.
 11. A methodas in claim 8, wherein the metformin hydrochloride is administered at adosage of between about 100 mg and about 2000 mg.
 12. A method as inclaim 8, wherein the compound of formula (I-X) or pharmaceuticallyacceptable salt thereof is administered at a dosage in the range of fromabout 50 mg to about 500 mg.
 13. A pharmaceutical composition comprising(a) metformin hydrochloride; (b) a compound of formula (I-X)

or a pharmaceutically acceptable salt thereof; and (c) apharmaceutically acceptable excipient.
 14. A pharmaceutical compositionsas in claim 13, wherein the metformin hydrochloride is present in anamount in the range of from about 100 mg to about 2000 mg; and whereinthe compound of formula (I-X) or pharmaceutically acceptable saltthereof is present in an amount in the range of from about 50 mg toabout 500 mg.
 15. A pharmaceutical composition as in claim 13, whereinthe metformin hydrochloride is present in an amount of about 250 mg,about 500 mg, about 750 mg, about 850 mg, or about 1000 mg; and whereinthe compound of formula (I-X) or pharmaceutically acceptable saltthereof is present in an amount of about 100 mg, about 150 mg or about300 mg.
 16. A pharmaceutical composition comprising (a) metformin or apharmaceutically acceptable salt thereof; (b) a compound of formula(I-X)

or pharmaceutically acceptable salt thereof; (c) a sulfonylurea orpharmaceutically acceptable salt thereof; and (d) a pharmaceuticallyacceptable excipient.
 17. A pharmaceutical composition as in claim 16,wherein the sulfonylurea is selected from the group consisting ofchlorpropamide, tolazamide, tolbutamide, glyburide, glipizide andglimepiride.
 18. A pharmaceutical composition as in claim 16, whereinthe metformin or pharmaceutically acceptable salt thereof is metforminhydrochloride; and wherein the sulfonylurea is glyburide.
 19. Apharmaceutical composition as in claim 16, wherein the metforminhydrochloride is present in an amount in the range of from about 100 mgto about 2000 mg; the compound of formula (I-X) or pharmaceuticallyacceptable salt thereof is present in an amount in the range of fromabout 50 mg to about 500 mg; and the glyburide is present in an amountin the range of form about 2.5 mg to about 20 mg.